Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Contributions of DNA interstrand cross-links to aging of cells and organisms

Contributions of DNA interstrand cross-links to aging of cells and organisms 7566–7576 Nucleic Acids Research, 2007, Vol. 35, No. 22 Published online 14 December 2007 doi:10.1093/nar/gkm1065 SURVEY AND SUMMARY Contributions of DNA interstrand cross-links to aging of cells and organisms Johannes Grillari*, Hermann Katinger and Regina Voglauer Aging and Immortalization Research (A.I.R.), Institute of Applied Microbiology, Department of Biotechnology, BOKU – University of Natural Resources and Applied Life Sciences, Vienna, Muthgasse 18 1190 Vienna, Austria Received August 7, 2007; Revised and Accepted November 11, 2007 ABSTRACT transcription and prevents the use of information encoded by the complementary strand for repair. Thus, ICL Impaired DNA damage repair, especially deficient formation poses a major challenge for the cellular repair transcription-coupled nucleotide excision repair, systems, also reflected by the fact that estimated 40 ICLs leads to segmental progeroid syndromes in human in repair deficient mammalian cells are sufficient to induce patients as well as in rodent models. Furthermore, cell death (2). ICLs are considered to be mainly sensed DNA double-strand break signalling has been pin- during replication in S-phase, where they lead to collapse pointed as a key inducer of cellular senescence. of replication forks and DSBs, while little is known on transcription-coupled sensing and repair of ICLs. Several recent findings suggest that another Surprisingly, ICL repair seems also absent in mitochon- DNA repair pathway, interstrand cross-link (ICL) drial DNA (3). repair, might also contribute to cell and organism The mechanisms that lead to repair of ICLs are still not aging. Therefore, we summarize and discuss well understood in mammalian cells, but two major here that (i) systemic administration of anti-cancer pathways have been identified. The minor pathway chemotherapeutics, in many cases DNA cross- depends on ERCC1/XPF and translesion bypass by linking drugs, induces premature progeroid frailty Rev3 and is error-prone (4). The major pathway depends in long-term survivors; (ii) that ICL-inducing again on ERCC1/XPF and error-free homologous recom- 8-methoxy-psoralen/UVA phototherapy leads to bination repair (5). Excellent recent reviews summarizing signs of premature skin aging as prominent long- ICL repair are available for yeast (6,7) as well as for term side effect and (iii) that mutated factors involved mammalian cells (8–11). While other DNA damage repair pathways like in ICL repair like ERCC1/XPF, the Fanconi anaemia transcription-coupled nucleotide excision repair (NER) proteins, WRN and SNEV lead to reduced replicative have well-established links to aging of cells, tissues and life span in vitro and segmental progeroid syndromes organisms (12), it is not yet clear if and to what extent in vivo. However, since ICL-inducing drugs cause ICLs are involved in causing or contributing to progeroid damage different from ICL and since all currently functional decline. Therefore, we here summarize several known ICL repair factors work in more than one findings suggesting that exogenous exposure to ICL pathway, further work will be needed to dissect the inducing agents or endogenous ICL repair deficiencies actual contribution of ICL damage to aging. are associated with signs of premature aging. PREMATURE AGING AS SIDE EFFECT OF INTRODUCTION CHEMOTHERAPIES Each human cell has to repair the large numbers of ICL inducing agents used in tumour therapy different DNA damages encountered each day: around 50 000 single-strand breaks (SSB), 10 double-strand Most of our current knowledge on ICL repair derives breaks (DSB), 10 000 depurinations, 600 depyrimidations, from the use of ICL-inducing chemicals in biochemical or 2000 oxidative lesions, 5000 alkylating lesions and 10 genetic analysis of cells and cell lines on the one hand and interstrand cross-linking events (1). Although rare, DNA from their wide and successful use as anticancer interstrand cross-links (ICLs) are among the most deadly chemotherapeutics (13) on the other hand. Common to types of damage. The cross-linking of the two comple- all of these chemical compounds is their bifunctional mentary DNA strands prevents replication as well as character that allows them to react with both DNA *To whom correspondence should be addressed. Tel: +43 1 36006 6230; Fax: +43 1 3697615; Email: Johannes.grillari@boku.ac.at 2007 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Nucleic Acids Research, 2007, Vol. 35, No. 22 7567 strands. Although this is widely accepted as major skin changes, chronic fatigue and sexual dysfunction (32) cytotoxic effect, it should be noted that the individual as well as cardiovascular complications (33). We therefore ICL-inducing agents induce different specific steric DNA- propose to refer to this side effect of chemotherapies as adduct structures and that they generate other than ICL acquired premature progeroid syndrome (APPS) in damage like DNA monoadducts, intrastrand cross-links, analogy to the term premature progeroid syndromes for damage to lipids, RNA and proteins. Furthermore, hereditary diseases that resemble accelerated aging (34). different reactive intermediates can be formed by cellular While it is clear that a large proportion of cancer metabolism. For a detailed review, see Ref. 7. The most patients received ICL-inducing chemotherapeutics, the important substance classes used in cancer therapies are data so far have not been apportioned according to briefly summarized in the following. the drugs used. Thus, it is not yet clear if and how the Platinum compounds, the most famous of which is individual cross-linking agents differ in their long-term cisplatinum diammine dichloride II (CDDP) was one of effects and if and how they differ from chemotherapeu- the first chemotherapeutics originally identified as inhib- tics with other modes of action. itor of bacterial cell division (14). Since then it has been Similarly, it is not yet clear what causes APPS as a long- used to treat a wide range of different tumours (15,16) and term side effect. One possibility is the exhaustion of second-generation drugs are intensely worked on (17). The proliferative potential of stem and progenitor cells as well damage to the DNA mainly consists of intrastrand cross- as of normal differentiated cells by the cytotoxic drugs. links as well as around 5–8% ICL of total adducts (18,19), In this scenario, DNA damage induces cellular senescence which are responsible for the main cytotoxic effects (20). and/or apoptosis in damaged cells, forcing the surround- Bis(2-chloroethyl)methylamine (HN2) and other mem- ing undamaged cells to undergo repeated proliferation in bers of the nitrogen mustard family are as well widely used order to maintain tissue homoeostasis. This idea is as anti-cancer drugs (21). Again the majority of damage supported by several observations. consists of monoadducts to the DNA, however, the 1–5% Increased apoptosis as well as senescence after che- ICLs are responsible for the high cytotoxicity (22). motherapy has been reported in many studies (35), and Oligonucleotides conjugated to nitrogen mustards can be senescent cells accumulate in different tissues and organs used to introduce ICLs at specific sites in the genome (23). with age (36–38) and even in tumours (39). One trigger of One of the most used chemotherapeutics of the senescence is critically short, uncapped telomeres (40) and nitrosurea class is bis(2-chloroethyl)nitrosurea (BCNU, indeed accelerated telomere shortening has been observed carmustine), which decomposes in aqueous phase to so far in chemotherapy-treated patients versus age-matched uncharacterized reactive bifunctional molecules (24). The controls (41). Furthermore, deficiencies in DNA repair number of ICLs formed by this drug is estimated to be have been shown to impair haematopoietic stem cell around 8% of all adducts, and again this seems to be the function (42) or to even deplete the pool of haematopoie- main cytotoxic component (25). tic stem cells with age (43). Therefore, APPS might be Mitomycin C (MMC) is a quinine-containing antibiotic caused by a general decline of tissue regeneration and isolated from streptomycetes. Only its intermediates that repair capacity in consequence to chemotherapy. are formed after several intracellular metabolic activation steps generate ICLs, which make up 5–14% of all adducts (26). The ICLs mainly affect dCpG sequences in the minor PSORALEN/UVA-INDUCED ICLs AND groove of DNA. A recent derivative, aziridinomitosene 4, PREMATURE SKIN AGING has been shown to have very high ICL-forming activity Psoralens belong to the furocoumarins, bifunctional without prior metabolization (27). Besides forming agents that form ICLs as well as thymine monoadducts adducts, MMC also induces production of reactive upon UVA activation and are among the most potent oxygen species (ROS), which also contributes to its interstrand cross-linking agents. Upon selection of differ- cytotoxicity (28). ent wavelengths up to 40% of the monoadducts can be Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) are a family converted to ICLs. Psoralen cytotoxicity is clearly linked of DNA interactive anti-tumour antibiotics derived from to ICL-forming activity, since exposure of cells to various Streptomyces species. One of the most promising psoralens with UV wavelengths that do not induce ICLs derivatives thereof is SJG-136, which displays a 440-fold or monofunctional psoralens not able to form ICLs are higher ICL formation activity than the nitrogen mustards markedly less toxic (44). (29,30). ICLs are targeted to the minor groove of the For studying response to and repair of specific ICLs, DNA even in a non-reductive environment (31). targeted single ICLs can be introduced into the genome using either oligonucleotides forming triplex DNA at the Early onset of progeroid frailty after chemotherapy complementary sites or peptide nucleic acids conjugated to Only now, after several decades of using ICL-inducing dimeric bis-psoralen (45,46). Furthermore, a digoxigenin- drugs in chemotherapy against cancer, sufficient patients 4,5’,8-trimethylpsoralen conjugate enables visualization of with more than 10 years survival are available for studying ICLs in cultured cells (47). long-term side effects. Several years after the initial The clinical conditions for which 8-methoxy-psoralen/ treatment, patients suffer from a variety of problems that UVA treatment (PUVA) has been widely and successfully usually occur later in life like decline of cognitive functions, used over decades are skin diseases like psoriasis, vitiligo visual deterioration, musculoskeletal decline, osteoporosis, and mycosis fungoides. The therapeutic effect depends on 7568 Nucleic Acids Research, 2007, Vol. 35, No. 22 formation of ICLs the massive formation of which has biosynthesis, and oxidative burst of immune cells. been observed in treated tissues (48). One prominent side Extrinsic sources like UV light, or heavy metal ions effect of repeated PUVA treatment is premature aging of contribute to ROS production as well (67). Free radicals have been postulated to be a major cause the skin (49–51). As a model to study the underlying mechanisms, human of aging in the ‘free radical theory of aging’ (68) and there is little doubt that ROS contribute to deterioration of cell fibroblasts and keratinoycytes have been subjected to (69) and organ function, e.g. brain (70), kidney (71,72), PUVA treatment. These studies suggest that premature liver (73) or heart (74). Increased formation of ROS (75), skin aging might be due to induction of a cellular lipid peroxidation products and reactive aldehydic mole- senescence programme triggered specifically by ICL cules (one of which would be malondialdehyde) has indeed formation (51–54) resembling a combined DNA damage been observed during aging (76–78). In addition, lipid and stress-induced phenotype at least at the transcrip- peroxidation products have been suggested as one tional level (55). parameter in a possible set of clinical aging markers (79). PUVA-induced senescence is signalled by ATR (56), However, direct evidence for an increase of malondial- whose importance for ICL repair is emphasized by data dehyde and in consequence malondialdehyde-ICLs has from Saccharomyces cerevisiae. Yeast ATR’s homologue not yet been provided, since the age-comparative studies Mec1 is activated by the heterotrimeric Rad17– so far were based on quantification of the bulk of reactive Mec3–Ddc1 complex (57). Surprisingly, MEC3 has aldehydes only, e.g. using thiobarbituric acid reactive recently been identified to be allelic to Pso9, mutations substances (TBARS) assay. in which render yeast cells sensitive to PUVA (58). Might there also be a difference between fast induction Furthermore, the human Rad17–Mec3–Ddc1 homologue of ICLs versus slow gradual increase as expected during called Rad9/Rad1/Hus1 (911) complex localizes to telo- aging due to gradual ROS increase (80,81)? Two studies meres and modulates telomere length and telomerase suggest that slow accumulation of DNA damage indeed activity (59). results in higher cytotoxicity than short-term high-dose While in the short-term cell cycle arrest is telomere- exposure. In the first study, HCT 116 cells were treated for independent, after 28 days after recovery from PUVA 24 h with low doses of the ICL-inducing agent SJG-136, treatment, senescence is still maintained with DNA leading to gradual formation of ICLs, and limited damage foci persisting mainly at telomeres as detected p21-induced cell cycle arrest. This resulted in significantly by co-staining of g-H2AX with telomere-specific fluores- higher cytotoxicity than a 1 h treatment with high doses of cence in situ hybridization. In contrast, intrachromosomal SJG-136 that caused full DNA damage response, although DNA damage has largely been repaired during the dose and time of treatment were carefully chosen to yield recovery (56). It is not clear why the damage foci persist similar final levels of ICLs within the cells (82). Similarly, at the telomeres and what might be the nature of this in the second study, low doses versus high doses of the damage. In this regard, it is of interest that telomeric DNA-damaging agents, hydroxyurea and UV were t-loops are efficiently maintained after psoralen cross- compared in three cell lines partially deficient in different linking (60), and that telomeric sequence contains the TA components of ATR-mediated signalling. Again, low basepairing within the TTAGGG repeats that are prime doses were found to cause significantly more cell death targets of 8-methoxypsoralen (61). This suggests that the accompanied with slow/insufficient activation of damage telomeres might be exquisitely susceptible to ICLs and signalling and repair (83). that PUVA treatment might cause more ICL per kilobase DNA at the telomere than within genomic sequences, and/ or that ICL repair is less efficient at the telomeres. ICL REPAIR DEFICIENCY CONTRIBUTES TO Besides senescence, apoptosis might be involved in the SIGNS OF ACCELERATED AGING reduction of the proliferative capacity of skin cells, since in vitro and in vivo PUVA has been shown to induce Although ICL repair is still not fully understood in higher apoptosis in epidermal cells via p53 and Fas ligand (62). eukaryotic cells, several central players have been identi- fied during the last years including, ERCC1/XPF, the Fanconi anaemia proteins, but also the RecQ helicases DOES ENDOGENOUS FORMATION OF ICLs WRN and BLM. Patients and corresponding animal INCREASE WITH AGE? models with mutations in these factors display various grades of segmental progeroid syndromes. In addition, So far, ICL formation by exogenous sources is undoubted, other factors contributing to ICL repair like SNM1/hPso2 but how do ICLs arise spontaneously within cells and or SNEV have been connected to cellular aging and tissues? One of the few currently known endogenously telomere biology. However, it has to be kept in mind that generated molecules causing ICLs is the bifunctional lipid all of the ICL factors described so far work in more than peroxidation product malondialdehyde. Various studies one DNA repair pathway or exert more than one have identified specific cross-link structures by malondial- function. dehyde with DNA in vitro (63) as well as in vivo in a variety of human tissues (64–66). ERCC1/XPF ROS necessary for peroxidation of lipids to malondial- dehyde arise from intrinsic cellular pathways, above all ERCC1/XPF is a structure-specific heterodimeric endo- from cell respiration, but also during prostaglandin nuclease essential in NER, but also during ICL repair. Nucleic Acids Research, 2007, Vol. 35, No. 22 7569 Incisions near the ICL site that ‘unhook’ the cross-linked IGF1 signalling was found in livers of ERCC1-deficient oligonucleotide specifically depend on ERCC1/XPF mice (96). Similar suppression of the IGF1/GH axis is seen (84,85). Mutations in both of its subunits have been after exposure of wild-type mice to chronic genotoxic found to cause segmental progeroid syndromes in stress using MMC (96). This would suggest that high humans. Similarly, mouse models deficient in ERCC1 levels of ICL damage provide a feedback signal to (86,87) as well as in XPF (88) show a congruent severe suppress growth at the organism level, probably in order progeroid phenotype that is quite distinct in severity from to allocate more energy to cellular maintenance and repair –/– most other mouse models deficient in NER only. ERCC in order to prolong the life span (96). Absence of IGF1 mice show ataxia, kyphosis, osteopenia, weight loss, skin suppression in XPA or Cockayne syndrome B-deficient atrophy, sarcopenia and hepatocellular polyploidization mice would argue against ERCC1’s NER function as (89) and the fibroblasts are exquisitely sensitive to cross- reason for developing progeroid phenotypes. It would be linking agents but also to UV light (87). interesting to test if impaired IGF1-signalling back- Recently, the first patient deficient in ERCC1 has been grounds [e.g. in Ames or Snell dwarf mice (102)] would identified, displaying a severe disease phenotype of additionally reduce the life span and increase severity or cerebro-oculo-facio-skeletal syndrome that also in part accelerate the appearance of progeroid symptoms resembles premature aging and resulted in early death observed with ICL repair deficiency. (90). In contrast to the knockout mouse model, cells of Further contributions to a premature aging phenotype this patient, showed only intermediate sensitivity to UV might derive from increased apoptosis as observed in liver –/– and MMC treatment, comparable to other NER-deficient tissue (103), decreased replicative potential of ERCC1 cells (90). embryonic fibroblasts (87) as well as depletion of This finding suggests that XPF/ERCC1 functions hematopoietic stem cells, which again is not observed in besides NER repair might confer the severity of the XPA mutant mice (104). mutation. Indeed, XPF/ERCC1 is required for meiotic An experimental setting that might allow for addressing and mitotic homologous recombination in mouse and fly ERCC1 deficiency in humans possibly arises from the (91,92) and also implicated in telomere processing, finding that ERCC1 is transcriptionally repressed by responsible for removing the 3’ overhang of uncapped fludarabine treatment (105,106), and increases ICLs telomeres (93). Surprisingly, the endonuclease function synergistically with cisplatin or oxaliplatin (107,108). required for both ICL and NER is separated from the Fludarabine is a chemotherapeutic drug mainly used telomere processing function of XPF, since a point against haematological malignancies (109). It would be of mutation that abrogates DNA repair does not interfere interest to analyse if this drug also leads to APPS in long- with 3’ overhang removal in cell culture experiments (94). term survivors. Furthermore, NER and ICL repair functions of XPF might be separable as well (95). This is consistent with the clinical appearance of the FA pathway currently known XPF mutations. Most of them result in FA is a disorder showing developmental and bone marrow mild forms of xeroderma pigmentosa (XP), a cancer-prone defects, as well as cancer predisposition (110). This rare syndrome characterized by high UV sensitivity. In hereditary disease is caused by mutations in one of contrast, one patient with a dramatic progeroid phenotype currently 13 proteins constituting 13 complementation has been identified bearing a novel mutation in XPF groups [FANCA, B, C, E, F, G, L and M forming a core (R153P9) interfering with formation of ERCC1 hetero- complex, D1, D2(BRCA2), H, I, J]. FAAP24 has recently dimers (96). Primary fibroblasts of this patient are much been proven as an additional FA complex member, more sensitive to ICL-inducing MMC as compared to although it has not been found mutated in FA patients XPA-derived cells, while they are only similarly sensitive yet (111). Recent progress in understanding the functions to UV irradiation (96). This finding would also support a of FA proteins and the ‘FA pathway’ has been reviewed in specific role of deficient ICL repair distinct from NER detail (9–11,112,113). deficiency in accelerating the aging process. Clearly, Although not being ranked among the segmental further work is required for dissecting the contributions progeroid syndromes in the initial listing by George of different mutations in XPF and ERCC1 in the observed Martin (34), there still seems to be a segmental premature progeroid features. It would for example be of high aging component in FA. This consists of progressive bone interest, to complement XPF-deficient mice with con- marrow failure, squamous cell carcinomas of the oral structs harbouring the various mutants, to see if and to cavity and genital area much earlier in life than in normal what extent ICL, NER, and dysfunctional telomere individuals, impaired gametogenesis and premature repro- processing of XPF contribute to their progeroid ductive aging. Additionally, >80% of FA patients are phenotype. prematurely affected by endocrine abnormalities including A completely different and much unexpected link hyperinsulinaemia, hypothyroidism and growth hormone between ERRC1 deficiency and aging has been discovered deficiency, all of which are normally associated with recently. Suppression of IGF1 signalling is one of the very advanced age (114). Decline of growth hormone is of note, few conserved mechanisms that prolongs life span in a wide range of model organisms from S. cerevisiae (97), since this leads to less IGF signalling similar to ERCC1/ Caenorhabditis elegans (98), Dorsophila melanogaster (99), XPF deficiency, supporting the idea of a general switch and mouse (100,101). Surprisingly, this suppression of from growth to repair upon (ICL?) damage. 7570 Nucleic Acids Research, 2007, Vol. 35, No. 22 Furthermore, cells of FA patients show signs of WRN activity might be necessary at different points of accelerated cellular senescence. PBMCs have accelerated ICL repair. It interacts with the SNEV-complex (see below) in early steps of repairing single psoralen ICLs individual annual telomere-shortening rates in vivo in vitro (138), while in the later HR repair step it interacts (115–117) while fibroblasts derived from FA patients with a complex containing Rad51, ATR, Rad54 and show accelerated telomere shortening in vitro (118), Rad54B (139) localizing to stalled replication forks (140). consistent with a reduced replicative life span and earlier entry into cellular senescence (119,120). This accelerated Another protein–protein interaction linking WRN to ICL telomere erosion, however, is not due to faster replicative repair derives from yeast, where its homologue sgs1 shortening, but to increased telomere breakage (121). interacts with Pso5/rad16 (141), involved in ICL repair and global NER (142). Together with an increase in apoptosis of haematopoietic A second RecQ helicase family member, which also stem cells (122,123), this might also contribute to the physically and functionally interacts with WRN (143), progressive bone marrow failure in patients (124) as well is BLM. Fibroblasts derived from Bloom’s syndrome as in knockout mouse models (125–127). patients show sensitivity to MMC treatment (144) To what extent are the FA proteins involved in ICL and to cisplatin (145). Both helicases have also been repair? While indeed hypersensitivity against ICLs by found to interact with members of the FA complex MMC and diepoxybutane is a common hallmark of all subunits and with HR factors (137,146–148). FA cells and used as standard diagnosis of FA, there is a Furthermore, FA core complex assembly is necessary broad spectrum of additional sensitivities against geno- for BLM phosphorylation and localization to nuclear foci toxic damage including g-irradiation, bleomycin, UV and upon ICLs (144). The unwinding activity of BLM also methyl methane sulphate depending on the cell type of the enhances Mus81 endonuclease activity (149), which same patient (128) as well as on the complementation converts ICLs to DSBs (150). Genetic interaction group (129). For example, FANCG null Chinese hamster between Mus81 and BLM homologues in D. melanogaster ovary (CHO) cells are similarly sensitive against mono- further supports their function in a common alkylating agents as against ICL-inducing agents (130). pathway (151). Furthermore, monoubiquitination of FANCD2, a crucial Mutations in both helicases cause prominent segmental step in activation of the ‘FA protein pathway’ is also progeroid syndromes. WRN mutations are the cause of induced by chemically blocking replication forks (131). Werner syndrome (152). High genomic instability is These findings led to the proposal that the FA proteins— observed in cells of Werner syndrome patients due to rather than being specifically necessary for ICL—might massive loss of telomeric sequences during replication act more globally on stabilizing collapsed replication forks (153), also leading to a reduced replicative life span in vitro that do not exclusively arise due to ICL (11). Collapse (154). of replication forks leads to formation of DSB, which Similarly, Bloom syndrome, is prominently ranked have recently been suggested to be a prerequisite for among the segmental progeroid disorders (152) and HR-dependent repair of ICL (132). The FA proteins BLM, like WRN, is necessary for telomere functionality might prevent the DSBs from being repaired by non- (155). Again, a clear attribution of accelerated aging to homologous end joining by keeping the broken strands in ICLs is not possible in the background of WRN and BLM close proximity. Thus, the FA pathway might largely mutations, since their functions are not limited to ICL counteract genomic instabilities by favouring base sub- repair. stitutions and small deletions over larger deletions and chromosomal rearrangements (10,11,133). Still, FA pro- hPSO2 (SNM1) teins are needed together with Msh2, ERCC1/XPF and Rev3 in HR-dependent repair of single psoralen-induced The nomenclature of the Pso genes is derived from ICLs (132). yeast cells displaying sensitivity to 8-methoxy-psoralen/ Further work is necessary to dissect if and to what UVA treatment (142). Yeast Pso2 is involved in trans- extent reduced ICL repair, failed stabilization of replica- lesion synthesis repair of ICL during G1 (156). The five tion forks or other DNA damage contribute to the homologues in humans are SNM1, SNM1B/Apollo, and progeroid symptoms in FA. To further complicate SNM1C/Artemis, ELAC2 and CPSF73, all of them things, FA cells also show elevated ROS levels and containing a b-CASP/metallo-b-lactamase domain (157). increased sensitivity against ROS (123). Therefore, it Sensitivity to ICL has been established for SNM1 in cannot be excluded that ROS cause or additively knockout mice (158) and for SNM1B/Apollo in human contribute to premature aging in FA patients. cells by siRNA-mediated knockdown (159). SNM1 knockout mice-derived cells show MMC sensitivity (158) as well as increased tumour incidence and immune BLM and WRN helicases deficiency (160). However, only weak resemblance to Besides its function in base excision DNA repair (134), the aging is observed in these mice. RecQ helicase member WRN has also been implicated in The second homologue, SNM1B/Apollo interacts with ICL repair. Cells from Werner syndrome patients show TRF2 and thus localizes to telomeres (161–163). Its sensitivity to ICL-inducing drugs (135,136) and WRN knockdown in human fibroblasts leads to rapid loss of helicase activity has been shown necessary for repair of telomeric sequences, accelerated entry into replicative PUVA-induced ICLs (137). senescence and formation of g-H2AX DNA damage Nucleic Acids Research, 2007, Vol. 35, No. 22 7571 Figure 1. Overview of a proposed contribution of DNA interstrand cross-links (ICLs) to aging: increased formation of ICLs leads to acquired premature progeroid syndrome (APPS) by exhaustion of replicative potential of stem and progenitor as well as normal cells, while suppression of IGF1 signalling redirects energy from growth to repair and maintenance. foci. If SNM1B/Apollo mutations also affect organismal (178), again makes it very difficult to dissect if its aging has not been analysed yet. ICL repair function is connected to cellular aging. If SNEV haploinsufficient mice show premature progeroid symptoms and reduced life span like the SAMP8 mice is SNEV (hPSO4) currently under investigation. The SNEV core complex consisting of CDC5L, SNEV (hPSO4, hNMP200, hPRP19), SPF27 (BCAS1) and CONCLUSIONS PLRG1 together with WRN helicase is essential in early steps of ICL repair in vitro using single psoralen Three different types of conditions that induce increased cross-linked plasmids as substrate for fractionated HeLa levels of ICLs have been summarized here: chemother- nuclear extracts (138). Furthermore SNEV binds dsDNA apeutic treatment of cancer using ICL-inducing drugs, and might accumulate upon MMC, but also upon PUVA treatment of skin diseases and increase of g-irradiation and bleomycin treatment in cell cultures endogenously formed ICLs by impaired ICL repair. All (164), while it clearly is ubiquitinated upon MMC and of these conditions lead to more or less pronounced methyl-methan-sulphonate treatment (165). progeroid features, clearly indicating that DNA damage is SNEV’s involvement in DNA repair is consistent with among the driving forces of aging and age-associated the role of its yeast orthologue Pso4 (Prp19) (166,167), pathologies. Although it seems clear that ICLs contribute where the temperature-sensitive mutant strain pso4-1 to aging-like loss of functions, their specific contribution displays a pleiotropic phenotype that includes sensitivity remains unknown due to the facts that all ICL-inducing to 8-methoxy-psoralen/UVA treatment (168). In yeast, drugs cause additional damage other than ICL and all Pso4 has been assigned to epistasis groups rad6 and rad52, currently known proteins involved in ICL repair have emphasizing its pleiotropic nature (169,170). other functions as well. Similarly, several other factors How is SNEV connected to aging? It was originally conferring hypersensitivity to ICL-inducing agents have isolated as mRNA that decreases during replicative not been linked to aging yet, e.g. the other Pso proteins senescence of endothelial cells (171), while upon over- like Pso1/Rev3 or the Rad51 paralogues XRCC2, XRCC3 expression it extends the replicative life span and reduces and Rad51C. basal apoptotic levels (172). Targeted disruption of SNEV How is ICL damage translated to aging of organisms? is early embryonic lethal, but haploinsufficiency causes A major contributor might be the exhaustion of replicative mouse embryonic fibroblasts to enter early into replicative potential of stem, progenitor and normal cells due to senescence in vitro (173). In addition, we recently found a increased apoptosis and senescence upon damage, while decrease in the self-renewal capacity of haematopoietic suppression of the IGF1 signalling might be a counter- +/– stem cells derived from SNEV mice as well as from active measure aimed at funnelling energy to repair and senescence accelerated SAMP8 mice. Haematopoietic maintenance of the damaged cells as summarized in our stem cells from both have significantly reduced SNEV model (Figure 1). levels as compared to wild-type or long-lived SAMR1 While our model is consistent with the idea that aging is controls (174). This further supports a link between DNA accelerated by stochastic damage but counteracted by repair, low replicative life span and the regenerative genetically programmed repair (179), it is so far only capacity of stem cells. based on induction of premature progeroid syndromes However, the multiplicity of SNEV’s functions as an and shortening of life span. An important unanswered essential pre-mRNA splicing factor (167,175), as ubiquitin question therefore is if reduced ICL induction or E3 ligase (176,177) and lipid droplet-binding protein improved ICL repair, e.g. by overexpression of ICL 7572 Nucleic Acids Research, 2007, Vol. 35, No. 22 indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] repair factors would be able to prolong the life and health (KP1019 or FFC14A). J. Inorg. Biochem., 100, 891–904. span of organisms. 18. Brabec,V. and Leng,M. (1993) DNA interstrand cross-links of trans-diamminedichloroplatinum(II) are preferentially formed between guanine and complementary cytosine residues. Proc. Natl Acad. Sci. USA, 90, 5345–5349. ACKNOWLEDGEMENTS 19. Jones,J.C., Zhen,W.P., Reed,E., Parker,R.J., Sancar,A. and This work was supported by grant NRN-S09306 of the Bohr,V.A. (1991) Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster Austrian Science Fund (FWF) and by Polymun Scientific ovary cells. J. Biol. Chem., 266, 7101–7107. GmbH, Vienna, Austria. We especially want to acknowl- 20. Roberts,J.J. and Friedlos,F. (1987) Quantitative estimation of edge our reviewers for generously providing helpful cisplatin-induced DNA interstrand cross-links and their repair in comments on this manuscript. Funding to pay the Open mammalian cells: relationship to toxicity. Pharmacol. Ther., 34, 215–246. Access publication charges for this article was provided 21. Balcome,S., Park,S., Quirk Dorr,D.R., Hafner,L., Phillips,L. and by Austrian Science Fund (FWF). Tretyakova,N. (2004) Adenine-containing DNA–DNA cross- links of antitumor nitrogen mustards. Chem. Res. Toxicol., Conflict of interest statement. None declared. 17, 950–962. 22. Rink,S.M. and Hopkins,P.B. (1995) A mechlorethamine-induced DNA interstrand cross-link bends duplex DNA. Biochemistry, 34, 1439–1445. REFERENCES 23. Singer,M.J., Podyminogin,M.A., Metcalf,M.A., Reed,M.W., 1. Lindahl,T. and Barnes,D.E. (2000) Repair of endogenous DNA Brown,D.A., Gamper,H.B., Meyer,R.B. and Wydro,R.M. (1999) damage. Cold Spring Harb. Symp. Quant. Biol., 65, 127–133. Targeted mutagenesis of DNA with alkylating RecA assisted 2. Akkari,Y.M., Bateman,R.L., Reifsteck,C.A., Olson,S.B. and oligonucleotides. Nucleic Acids Res., 27, e38. Grompe,M. (2000) DNA replication is required to elicit cellular 24. Colvin,M., Cowens,J.W., Brundrett,R.B., Kramer,B.S. and responses to psoralen-induced DNA interstrand cross-links. Ludlum,D.B. (1974) Decomposition of BCNU (1,3-bis Mol. Cell. Biol., 20, 8283–8289. (2-chloroethyl)-1-nitrosourea) in aqueous solution. Biochem. 3. Cullinane,C. and Bohr,V.A. (1998) DNA interstrand cross-links Biophys. Res. Commun., 60, 515–520. induced by psoralen are not repaired in mammalian mitochondria. 25. Wiencke,J.K. and Wiemels,J. (1995) Genotoxicity of 1,3-bis Cancer Res., 58, 1400–1404. (2-chloroethyl)-1-nitrosourea (BCNU). Mutat. Res., 339, 91–119. 4. Shen,X., Jun,S., O’Neal,L.E., Sonoda,E., Bemark,M., Sale,J.E. and 26. Seow,H.A., Penketh,P.G., Baumann,R.P. and Sartorelli,A.C. (2004) Li,L. (2006) REV3 and REV1 play major roles in recombination- Bioactivation and resistance to mitomycin C. Methods Enzymol., independent repair of DNA interstrand cross-links mediated by 382, 221–233. monoubiquitinated proliferating cell nuclear antigen (PCNA). 27. Rink,S.M., Warner,D.L., Klapars,A. and Vedejs,E. (2005) J. Biol. Chem., 281, 13869–13872. Sequence-specific DNA interstrand cross-linking by an aziridino- 5. Collins,A.R. (1993) Mutant rodent cell lines sensitive to ultraviolet mitosene in the absence of exogenous reductant. Biochemistry, light, ionizing radiation and cross-linking agents: a comprehensive 44, 13981–13986. survey of genetic and biochemical characteristics. Mutat. Res., 28. Pagano,G. (2002) Redox-modulated xenobiotic action and 293, 99–118. ROS formation: a mirror or a window? Hum. Exp. Toxicol., 6. Dronkert,M.L. and Kanaar,R. (2001) Repair of DNA interstrand 21, 77–81. cross-links. Mutat. Res., 486, 217–247. 29. Gregson,S.J., Howard,P.W., Gullick,D.R., Hamaguchi,A., 7. Lehoczky,P., McHugh,P.J. and Chovanec,M. (2007) DNA inter- Corcoran,K.E., Brooks,N.A., Hartley,J.A., Jenkins,T.C., Patel,S. strand cross-link repair in Saccharomyces cerevisiae. FEMS et al. (2004) Linker length modulates DNA cross-linking reactivity Microbiol. Rev., 31, 109–133. and cytotoxic potency of C8/C8’ ether-linked C2-exo-unsaturated 8. Niedernhofer,L.J., Lalai,A.S. and Hoeijmakers,J.H. (2005) Fanconi pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers. J. Med. Chem., anemia (cross)linked to DNA repair. Cell, 123, 1191–1198. 47, 1161–1174. 9. Levitus,M., Joenje,H. and de Winter,J.P. (2006) The Fanconi 30. Gregson,S.J., Howard,P.W., Hartley,J.A., Brooks,N.A., anemia pathway of genomic maintenance. Cell Oncol., 28, 3–29. Adams,L.J., Jenkins,T.C., Kelland,L.R. and Thurston,D.E. (2001) 10. Kennedy,R.D. and D’Andrea,A.D. (2005) The Fanconi anemia/ Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine BRCA pathway: new faces in the crowd. Genes Dev., 19, 2925–2940. DNA-interactive agent with highly efficient cross-linking ability and 11. Thompson,L.H., Hinz,J.M., Yamada,N.A. and Jones,N.J. (2005) potent cytotoxicity. J. Med. Chem., 44, 737–748. How Fanconi anemia proteins promote the four Rs: replication, 31. Martin,C., Ellis,T., McGurk,C.J., Jenkins,T.C., Hartley,J.A., recombination, repair, and recovery. Environ. Mol. Mutagen., Waring,M.J. and Thurston,D.E. (2005) Sequence-selective interac- 45, 128–142. tion of the minor-groove interstrand cross-linking agent SJG-136 12. Mitchell,J.R., Hoeijmakers,J.H. and Niedernhofer,L.J. (2003) with naked and cellular DNA: footprinting and enzyme inhibition Divide and conquer: nucleotide excision repair battles cancer and studies. Biochemistry, 44, 4135–4147. ageing. Curr. Opin. Cell. Biol., 15, 232–240. 32. Maccormick,R.E. (2006) Possible acceleration of aging by adjuvant 13. McHugh,P.J., Spanswick,V.J. and Hartley,J.A. (2001) Repair of chemotherapy: a cause of early onset frailty? Med. Hypotheses, DNA interstrand crosslinks: molecular mechanisms and clinical 67, 212–215. relevance. Lancet Oncol., 2, 483–490. 33. Meinardi,M.T., Gietema,J.A., van Veldhuisen,D.J., van der 14. Rosenberg,B., Vancamp,L. and Krigas,T. (1965) Inhibition of cell Graaf,W.T., de Vries,E.G. and Sleijfer,D.T. (2000) Long-term division in Escherichia coli by electrolysis products from a platinum chemotherapy-related cardiovascular morbidity. Cancer Treat. Rev., electrode. Nature, 205, 698–699. 26, 429–447. 15. Boulikas,T. and Vougiouka,M. (2004) Recent clinical trials using 34. Martin,G.M. (1978) Genetic syndromes in man with potential cisplatin, carboplatin and their combination chemotherapy drugs relevance to the pathobiology of aging. Birth Defects Orig. Artic. (review). Oncol. Rep., 11, 559–595. Ser., 14, 5–39. 16. Galanski,M., Jakupec,M.A. and Keppler,B.K. (2005) Update of the 35. Roninson,I.B. (2002) Tumor senescence as a determinant of drug preclinical situation of anticancer platinum complexes: novel design response in vivo. Drug Resist. Updat., 5, 204–208. strategies and innovative analytical approaches. Curr. Med. Chem., 36. Herbig,U., Ferreira,M., Condel,L., Carey,D. and Sedivy,J.M. (2006) 12, 2075–2094. Cellular senescence in aging primates. Science, 311, 1257. 17. Hartinger,C.G., Zorbas-Seifried,S., Jakupec,M.A., Kynast,B., 37. Erusalimsky,J.D. and Kurz,D.J. (2005) Cellular senescence in vivo: Zorbas,H. and Keppler,B.K. (2006) From bench to bedside – Its relevance in ageing and cardiovascular disease. Exp. Gerontol., preclinical and early clinical development of the anticancer agent 40, 634–642. Nucleic Acids Research, 2007, Vol. 35, No. 22 7573 38. Halloran,P.F. and Melk,A. (2001) Renal senescence, cellular pso9-1 of Saccharomyces cerevisiae contains a mutant allele of the senescence, and their relevance to nephrology and transplantation. DNA damage checkpoint gene MEC3. DNA Repair, 5, 163–171. Adv. Nephrol. Necker Hosp., 31, 273–283. 59. Francia,S., Weiss,R.S., Hande,M.P., Freire,R. and d’Adda di 39. Van Nguyen,T., Puebla-Osorio,N., Pang,H., Dujka,M.E. and Fagagna,F. (2006) Telomere and telomerase modulation by the Zhu,C. (2007) DNA damage-induced cellular senescence is sufficient mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex. to suppress tumorigenesis: a mouse model. J. Exp. Med., Curr. Biol., 16, 1551–1558. 204, 1453–1461. 60. Griffith,J.D., Comeau,L., Rosenfield,S., Stansel,R.M., Bianchi,A., 40. de Lange,T. (2005) Shelterin: the protein complex that shapes and Moss,H. and de Lange,T. (1999) Mammalian telomeres end in a safeguards human telomeres. Genes Dev., 19, 2100–2110. large duplex loop. Cell, 97, 503–514. 41. Beeharry,N. and Broccoli,D. (2005) Telomere dynamics in response 61. Van Houten,B., Gamper,H., Hearst,J.E. and Sancar,A. (1986) to chemotherapy. Curr. Mol. Med., 5, 187–196. Construction of DNA substrates modified with psoralen at a unique 42. Rossi,D.J., Bryder,D., Seita,J., Nussenzweig,A., Hoeijmakers,J. and site and study of the action mechanism of ABC excinuclease on Weissman,I.L. (2007) Deficiencies in DNA damage repair limit the these uniformly modified substrates. J. Biol. Chem., function of haematopoietic stem cells with age. Nature, 261, 14135–14141. 447, 725–729. 62. Santamaria,A.B., Davis,D.W., Nghiem,D.X., McConkey,D.J., 43. Nijnik,A., Woodbine,L., Marchetti,C., Dawson,S., Lambe,T., Ullrich,S.E., Kapoor,M., Lozano,G. and Ananthaswamy,H.N. Liu,C., Rodrigues,N.P., Crockford,T.L., Cabuy,E. et al. (2007) (2002) p53 and Fas ligand are required for psoralen and DNA repair is limiting for haematopoietic stem cells during ageing. UVA-induced apoptosis in mouse epidermal cells. Cell Death Nature, 447, 686–690. Differ., 9, 549–560. 44. Bethea,D., Fullmer,B., Syed,S., Seltzer,G., Tiano,J., Rischko,C., 63. Marnett,L.J. (2000) Oxyradicals and DNA damage. Carcinogenesis, Gillespie,L., Brown,D. and Gasparro,F.P. (1999) Psoralen photo- 21, 361–370. biology and photochemotherapy: 50 years of science and medicine. 64. Kadlubar,F.F., Anderson,K.E., Haussermann,S., Lang,N.P., J. Dermatol. Sci., 19, 78–88. Barone,G.W., Thompson,P.A., MacLeod,S.L., Chou,M.W., 45. Kim,K.H., Fan,X.J. and Nielsen,P.E. (2007) Efficient sequence- Mikhailova,M. et al. (1998) Comparison of DNA adduct levels directed psoralen targeting using pseudocomplementary Peptide associated with oxidative stress in human pancreas. Mutat. Res., nucleic acids. Bioconjug. Chem., 18, 567–572. 405, 125–133. 46. Kim,K.H., Nielsen,P.E. and Glazer,P.M. (2006) Site-specific gene 65. Sharma,R.A., Gescher,A., Plastaras,J.P., Leuratti,C., Singh,R., modification by PNAs conjugated to psoralen. Biochemistry, Gallacher-Horley,B., Offord,E., Marnett,L.J., Steward,W.P. et al. 45, 314–323. (2001) Cyclooxygenase-2, malondialdehyde and pyrimidopurinone 47. Thazhathveetil,A.K., Liu,S.T., Indig,F.E. and Seidman,M.M. (2007) adducts of deoxyguanosine in human colon cells. Carcinogenesis, Psoralen conjugates for visualization of genomic interstrand cross- 22, 1557–1560. links localized by laser photoactivation. Bioconjug. Chem., 66. Niedernhofer,L.J., Daniels,J.S., Rouzer,C.A., Greene,R.E. and 18, 431–437. Marnett,L.J. (2003) Malondialdehyde, a product of lipid peroxida- 48. Pathak,M.A., Zarebska,Z., Mihm,M.C.,Jr, Jarzabek- tion, is mutagenic in human cells. J. Biol. Chem., 278, 31426–31433. Chorzelska,M., Chorzelski,T. and Jablonska,S. (1986) Detection of 67. Esterbauer,H. (1993) Cytotoxicity and genotoxicity of lipid- DNA-psoralen photoadducts in mammalian skin. J. Invest. oxidation products. Am. J. Clin. Nutr., 57, 779S–785S, discussion. Dermatol., 86, 308–315. 68. Harman,D. (1956) Aging: a theory based on free radical and 49. Wolff,K. (1990) Side-effects of psoralen photochemotherapy radiation chemistry. J. Gerontol., 11, 298–300. (PUVA). Br J Dermatol, 122(Suppl. 36), 117–125. 69. de Magalhaes,J.P. and Church,G.M. (2006) Cells discover fire: 50. Sator,P.G., Schmidt,J.B. and Honigsmann,H. (2002) Objective employing reactive oxygen species in development and consequences assessment of photoageing effects using high-frequency ultrasound for aging. Exp. Gerontol., 41, 1–10. in PUVA-treated psoriasis patients. Br. J. Dermatol., 147, 291–298. 70. Droge,W. and Schipper,H.M. (2007) Oxidative stress and aberrant 51. Wlaschek,M., Ma,W., Jansen-Durr,P. and Scharffetter- signaling in aging and cognitive decline. Aging Cell, 6, 361–370. Kochanek,K. (2003) Photoaging as a consequence of natural and 71. Percy,C., Pat,B., Poronnik,P. and Gobe,G. (2005) Role of oxidative therapeutic ultraviolet irradiation–studies on PUVA-induced senes- stress in age-associated chronic kidney pathologies. Adv. Chronic cence-like growth arrest of human dermal fibroblasts. Exp. Kidney Dis., 12, 78–83. Gerontol., 38, 1265–1270. 72. Csiszar,A., Toth,J., Peti-Peterdi,J. and Ungvari,Z. (2007) The aging 52. Herrmann,G., Brenneisen,P., Wlaschek,M., Wenk,J., Faisst,K., kidney: role of endothelial oxidative stress and inflammation. Acta Quel,G., Hommel,C., Goerz,G., Ruzicka,T. et al. (1998) Psoralen Physiol. Hung., 94, 107–115. photoactivation promotes morphological and functional changes in 73. Anantharaju,A., Feller,A. and Chedid,A. (2002) Aging liver. a fibroblasts in vitro reminiscent of cellular senescence. J. Cell. Sci., review. Gerontology, 48, 343–353. 111(Pt 6), 759–767. 74. Rohrbach,S., Niemann,B., Abushouk,A.M. and Holtz,J. (2006) 53. Ma,W., Hommel,C., Brenneisen,P., Peters,T., Smit,N., Sedivy,J., Caloric restriction and mitochondrial function in the ageing Scharffetter-Kochanek,K. and Wlaschek,M. (2003) Long-term myocardium. Exp. Gerontol., 41, 525–531. growth arrest of PUVA-treated fibroblasts in G2/M in the absence 75. Van Remmen,H. and Richardson,A. (2001) Oxidative damage to of p16(INK4a) p21(CIP1) or p53. Exp. Dermatol., 12, 629–637. mitochondria and aging. Exp. Gerontol., 36, 957–968. 54. Ma,W., Wlaschek,M., Hommel,C., Schneider,L.A. and Scharffetter- 76. Carrera-Rotllan,J. and Estrada-Garcia,L. (1998) Age-dependent Kochanek,K. (2002) Psoralen plus UVA (PUVA) induced pre- changes and interrelations of number of cells and biochemical mature senescence as a model for stress-induced premature parameters (glucose, triglycerides, TBARS, calcium, phosphorus) in senescence. Exp. Gerontol., 37, 1197–1201. cultured human vein endothelial cells. Mech. Ageing Dev., 55. Borlon,C., Debacq-Chainiaux,F., Hinrichs,C., Scharffetter- 103, 13–26. Kochanek,K., Toussaint,O. and Wlaschek,M. (2007) The gene 77. Ando,K., Beppu,M. and Kikugawa,K. (1995) Evidence for accu- expression profile of psoralen plus UVA-induced premature mulation of lipid hydroperoxides during the aging of human red senescence in skin fibroblasts resembles a combined DNA-damage blood cells in the circulation. Biol. Pharm. Bull., 18, 659–663. and stress-induced cellular senescence response phenotype. Exp. 78. Stolzing,A., Sethe,S. and Scutt,A.M. (2006) Stressed stem cells: Gerontol, 42, 911–923. temperature response in aged mesenchymal stem cells. Stem Cells 56. Hovest,M.G., Bruggenolte,N., Hosseini,K.S., Krieg,T. and Dev., 15, 478–487. Herrmann,G. (2006) Senescence of human fibroblasts after psoralen 79. Voss,P. and Siems,W. (2006) Clinical oxidation parameters of aging. photoactivation is mediated by ATR kinase and persistent DNA Free Radic. Res., 40, 1339–1349. damage foci at telomeres. Mol. Biol. Cell, 17, 1758–1767. 80. Droge,W. (2002) Free radicals in the physiological control of cell 57. Majka,J. and Burgers,P.M. (2007) Clamping the Mec1/ATR function. Physiol. Rev., 82, 47–95. checkpoint kinase into action. Cell Cycle, 6, 1157–1160. 81. Wei,Y.H. and Lee,H.C. (2002) Oxidative stress, mitochondrial 58. Cardone,J.M., Revers,L.F., Machado,R.M., Bonatto,D., DNA mutation, and impairment of antioxidant enzymes in aging. Brendel,M. and Henriques,J.A. (2006) Psoralen-sensitive mutant Exp. Biol. Med., 227, 671–682. 7574 Nucleic Acids Research, 2007, Vol. 35, No. 22 82. Arnould,S., Spanswick,V.J., Macpherson,J.S., Hartley,J.A., life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science, 292, 104–106. Thurston,D.E., Jodrell,D.I. and Guichard,S.M. (2006) Time- 100. Flurkey,K., Papaconstantinou,J., Miller,R.A. and Harrison,D.E. dependent cytotoxicity induced by SJG-136 (NSC 694501): (2001) Lifespan extension and delayed immune and collagen aging influence of the rate of interstrand cross-link formation on DNA in mutant mice with defects in growth hormone production. damage signaling. Mol. Cancer Ther., 5, 1602–1609. 83. O’Driscoll,M., Dobyns,W.B., van Hagen,J.M. and Jeggo,P.A. Proc. Natl Acad. Sci. USA, 98, 6736–6741. 101. Bluher,M., Kahn,B.B. and Kahn,C.R. (2003) Extended longevity (2007) Cellular and Clinical Impact of Haploinsufficiency in mice lacking the insulin receptor in adipose tissue. Science, for Genes Involved in ATR Signaling. Am. J. Hum. Genet., 299, 572–574. 81, 77–86. 102. Bartke,A. (2005) Minireview: role of the growth hormone/ 84. Niedernhofer,L.J., Odijk,H., Budzowska,M., van Drunen,E., insulin-like growth factor system in mammalian aging. Maas,A., Theil,A.F., de Wit,J., Jaspers,N.G., Beverloo,H.B. et al. Endocrinology, 146, 3718–3723. (2004) The structure-specific endonuclease Ercc1-Xpf is required to 103. Kirschner,K., Singh,R., Prost,S. and Melton,D.W. (2007) resolve DNA interstrand cross-link-induced double-strand breaks. Characterisation of Ercc1 deficiency in the liver and in conditional Mol. Cell. Biol., 24, 5776–5787. Ercc1-deficient primary hepatocytes in vitro. DNA Repair, 85. Clingen,P.H., Arlett,C.F., Hartley,J.A. and Parris,C.N. (2007) 6, 304–316. Chemosensitivity of primary human fibroblasts with defective 104. Prasher,J.M., Lalai,A.S., Heijmans-Antonissen,C., unhooking of DNA interstrand cross-links. Exp. Cell Res., Ploemacher,R.E., Hoeijmakers,J.H., Touw,I.P. and 313, 753–760. Niedernhofer,L.J. (2005) Reduced hematopoietic reserves in DNA 86. McWhir,J., Selfridge,J., Harrison,D.J., Squires,S. and –/– interstrand crosslink repair-deficient Ercc1 mice. EMBO J., Melton,D.W. (1993) Mice with DNA repair gene (ERCC-1) 24, 861–871. deficiency have elevated levels of p53, liver nuclear abnormalities 105. Pepper,C., Lowe,H., Fegan,C., Thurieau,C., Thurston,D.E., and die before weaning. Nat. Genet., 5, 217–224. Hartley,J.A. and Delavault,P. (2007) Fludarabine-mediated sup- 87. Weeda,G., Donker,I., de Wit,J., Morreau,H., Janssens,R., pression of the excision repair enzyme ERCC1 contributes to the Vissers,C.J., Nigg,A., van Steeg,H., Bootsma,D. et al. (1997) cytotoxic synergy with the DNA minor groove crosslinking agent Disruption of mouse ERCC1 results in a novel repair syndrome SJG-136 (NSC 694501) in chronic lymphocytic leukaemia cells. with growth failure, nuclear abnormalities and senescence. Curr. Br. J. Cancer, 97, 253–259. Biol., 7, 427–439. 106. Yang,L.Y., Li,L., Keating,M.J. and Plunkett,W. (1995) 88. Tian,M., Shinkura,R., Shinkura,N. and Alt,F.W. (2004) Growth Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and retardation, early death, and DNA repair defects in mice deficient inhibits cisplatin-DNA cross-link repair. Mol. Pharmacol., for the nucleotide excision repair enzyme XPF. Mol. Cell. Biol., 47, 1072–1079. 24, 1200–1205. 107. Moufarij,M.A., Sampath,D., Keating,M.J. and Plunkett,W. (2006) 89. Hasty,P., Campisi,J., Hoeijmakers,J., van Steeg,H. and Vijg,J. Fludarabine increases oxaliplatin cytotoxicity in normal and (2003) Aging and genome maintenance: lessons from the mouse? chronic lymphocytic leukemia lymphocytes by suppressing inter- Science, 299, 1355–1359. strand DNA crosslink removal. Blood, 108, 4187–4193. 90. Jaspers,N.G., Raams,A., Silengo,M.C., Wijgers,N., 108. Li,L., Keating,M.J., Plunkett,W. and Yang,L.Y. (1997) Niedernhofer,L.J., Robinson,A.R., Giglia-Mari,G., Fludarabine-mediated repair inhibition of cisplatin-induced DNA Hoogstraten,D., Kleijer,W.J. et al. (2007) First reported patient lesions in human chronic myelogenous leukemia-blast crisis K562 with human ERCC1 deficiency has cerebro-oculo-facio-skeletal cells: induction of synergistic cytotoxicity independent of reversal syndrome with a mild defect in nucleotide excision repair and of apoptosis resistance. Mol. Pharmacol., 52, 798–806. severe developmental failure. Am. J. Hum. Genet., 80, 457–466. 109. Montillo,M., Ricci,F. and Tedeschi,A. (2006) Role of fludarabine 91. Radford,S.J., Goley,E., Baxter,K., McMahan,S. and Sekelsky,J. in hematological malignancies. Expert Rev. Anticancer Ther., (2005) Drosophila ERCC1 is required for a subset of MEI-9- 6, 1141–1161. dependent meiotic crossovers. Genetics, 170, 1737–1745. 110. Tischkowitz,M. and Dokal,I. (2004) Fanconi anaemia and 92. Shannon,M., Lamerdin,J.E., Richardson,L., leukaemia - clinical and molecular aspects. Br. J. Haematol., McCutchen-Maloney,S.L., Hwang,M.H., Handel,M.A., Stubbs,L. 126, 176–191. and Thelen,M.P. (1999) Characterization of the mouse Xpf DNA 111. Ciccia,A., Ling,C., Coulthard,R., Yan,Z., Xue,Y., Meetei,A.R., repair gene and differential expression during spermatogenesis. Laghmani el,H., Joenje,H., McDonald,N. et al. (2007) Genomics, 62, 427–435. Identification of FAAP24, a Fanconi anemia core complex protein 93. Zhu,X.D., Niedernhofer,L., Kuster,B., Mann,M., that interacts with FANCM. Mol. Cell, 25, 331–343. Hoeijmakers,J.H. and de Lange,T. (2003) ERCC1/XPF removes 112. Niedernhofer,L.J. (2007) The Fanconi anemia signalosome anchor. the 3’ overhang from uncapped telomeres and represses formation Mol. Cell, 25, 487–490. of telomeric DNA-containing double minute chromosomes. Mol. 113. Taniguchi,T. and D’Andrea,A.D. (2006) Molecular patho- Cell, 12, 1489–1498. genesis of Fanconi anemia: recent progress. Blood, 94. Wu,Y., Zacal,N.J., Rainbow,A.J. and Zhu,X.D. (2007) XPF with 107, 4223–4233. mutations in its conserved nuclease domain is defective in DNA 114. Schroeder-Kurth,T. (2007) Fanconi anemia. a paradigmatic repair but functions in TRF2-mediated telomere shortening. DNA. disease for the understanding of cancer and aging. Repair, 6, 157–166. In Schindler,D.H.H. (ed.), Monographic Human Genetics, Vol. 15; 95. Zhang,N., Zhang,X., Peterson,C., Li,L. and Legerski,R. (2000) Karger, Basel, pp. 1–8. Differential processing of UV mimetic and interstrand crosslink 115. Ball,S.E., Gibson,F.M., Rizzo,S., Tooze,J.A., Marsh,J.C. and damage by XPF cell extracts. Nucleic Acids Res., 28, 4800–4804. Gordon-Smith,E.C. (1998) Progressive telomere shortening in 96. Niedernhofer,L.J., Garinis,G.A., Raams,A., Lalai,A.S., aplastic anemia. Blood, 91, 3582–3592. Robinson,A.R., Appeldoorn,E., Odijk,H., Oostendorp,R., 116. Leteurtre,F., Li,X., Guardiola,P., Le Roux,G., Sergere,J.C., Ahmad,A. et al. (2006) A new progeroid syndrome reveals that Richard,P., Carosella,E.D. and Gluckman,E. (1999) Accelerated genotoxic stress suppresses the somatotroph axis. Nature, telomere shortening and telomerase activation in Fanconi’s 444, 1038–1043. anaemia. Br. J. Haematol., 105, 883–893. 97. Fabrizio,P., Pozza,F., Pletcher,S.D., Gendron,C.M. and 117. Hanson,H., Mathew,C.G., Docherty,Z. and Mackie Ogilvie,C. Longo,V.D. (2001) Regulation of longevity and stress resistance (2001) Telomere shortening in Fanconi anaemia by Sch9 in yeast. Science, 292, 288–290. demonstrated by a direct FISH approach. Cytogenet. Cell Genet., 98. Kenyon,C., Chang,J., Gensch,E., Rudner,A. and Tabtiang,R. 93, 203–206. (1993) A C. elegans mutant that lives twice as long as wild type. 118. Cabuy,E., Newton,C., Joksic,G., Woodbine,L., Koller,B., Nature, 366, 461–464. Jeggo,P.A. and Slijepcevic,P. (2005) Accelerated telomere short- 99. Clancy,D.J., Gems,D., Harshman,L.G., Oldham,S., Stocker,H., ening and telomere abnormalities in radiosensitive cell lines. Hafen,E., Leevers,S.J. and Partridge,L. (2001) Extension of Radiat. Res., 164, 53–62. Nucleic Acids Research, 2007, Vol. 35, No. 22 7575 119. Thompson,K.V. and Holliday,R. (1983) Genetic effects on the 139. Otterlei,M., Bruheim,P., Ahn,B., Bussen,W., Karmakar,P., longevity of cultured human fibroblasts. II. DNA repair deficient Baynton,K. and Bohr,V.A. (2006) Werner syndrome protein syndromes. Gerontology, 29, 83–88. participates in a complex with RAD51, RAD54, RAD54B and 120. Adelfalk,C., Lorenz,M., Serra,V., von Zglinicki,T., Hirsch- ATR in response to ICL-induced replication arrest. J. Cell. Sci., Kauffmann,M. and Schweiger,M. (2001) Accelerated telomere 119, 5137–5146. shortening in Fanconi anemia fibroblasts–a longitudinal study. 140. Dhillon,K.K., Sidorova,J., Saintigny,Y., Poot,M., Gollahon,K., FEBS Lett., 506, 22–26. Rabinovitch,P.S. and Monnat,R.J.Jr. (2007) Functional role of 121. Callen,E., Samper,E., Ramirez,M.J., Creus,A., Marcos,R., the Werner syndrome RecQ helicase in human fibroblasts. Ortega,J.J., Olive,T., Badell,I., Blasco,M.A. et al. (2002) Breaks at Aging Cell, 6, 53–61. telomeres and TRF2-independent end fusions in Fanconi anemia. 141. Saffi,J., Feldmann,H., Winnacker,E.L. and Henriques,J.A. (2001) Hum. Mol. Genet., 11, 439–444. Interaction of the yeast Pso5/Rad16 and Sgs1 proteins: influences 122. Bagby,G.C.,Jr (2003) Genetic basis of Fanconi anemia. Curr. on DNA repair and aging. Mutat. Res., 486, 195–206. Opin. Hematol., 10, 68–76. 142. Brendel,M., Bonatto,D., Strauss,M., Revers,L.F., Pungartnik,C., 123. Bogliolo,M., Cabre,O., Callen,E., Castillo,V., Creus,A., Marcos,R. Saffi,J. and Henriques,J.A. (2003) Role of PSO genes in repair of and Surralles,J. (2002) The Fanconi anaemia genome stability and DNA damage of Saccharomyces cerevisiae. Mutat. Res., tumour suppressor network. Mutagenesis, 17, 529–538. 544, 179–193. 124. Li,X., Leteurtre,F., Rocha,V., Guardiola,P., Berger,R., 143. von Kobbe,C., Karmakar,P., Dawut,L., Opresko,P., Zeng,X., Daniel,M.T., Noguera,M.H., Maarek,O., Roux,G.L. et al. (2003) Brosh,R.M.,Jr, Hickson,I.D. and Bohr,V.A. (2002) Colocalization, Abnormal telomere metabolism in Fanconi’s anaemia correlates physical, and functional interaction between Werner and Bloom with genomic instability and the probability of developing severe syndrome proteins. J. Biol. Chem., 277, 22035–22044. aplastic anaemia. Br. J. Haematol., 120, 836–845. 144. Pichierri,P., Franchitto,A. and Rosselli,F. (2004) BLM and the 125. Donoho,G., Brenneman,M.A., Cui,T.X., Donoviel,D., Vogel,H., FANC proteins collaborate in a common pathway in response to Goodwin,E.H., Chen,D.J. and Hasty,P. (2003) Deletion of Brca2 stalled replication forks. EMBO J., 23, 3154–3163. exon 27 causes hypersensitivity to DNA crosslinks, chromosomal 145. Slupianek,A., Gurdek,E., Koptyra,M., Nowicki,M.O., instability, and reduced life span in mice. Genes Chromosomes Siddiqui,K.M., Groden,J. and Skorski,T. (2005) BLM helicase is Cancer, 36, 317–331. activated in BCR/ABL leukemia cells to modulate responses to 126. Zhang,X., Li,J., Sejas,D.P. and Pang,Q. (2005) Hypoxia- cisplatin. Oncogene, 24, 3914–3922. reoxygenation induces premature senescence in FA bone marrow 146. Cheng,W.H., von Kobbe,C., Opresko,P.L., Arthur,L.M., hematopoietic cells. Blood, 106, 75–85. Komatsu,K., Seidman,M.M., Carney,J.P. and Bohr,V.A. (2004) 127. Zhang,X., Sejas,D.P., Qiu,Y., Williams,D.A. and Pang,Q. (2007) Linkage between Werner syndrome protein and the Mre11 Inflammatory ROS promote and cooperate with the Fanconi complex via Nbs1. J. Biol. Chem., 279, 21169–21176. anemia mutation for hematopoietic senescence. J. Cell. Sci., 147. Hirano,S., Yamamoto,K., Ishiai,M., Yamazoe,M., Seki,M., 120, 1572–1583. Matsushita,N., Ohzeki,M., Yamashita,Y.M., Arakawa,H. et al. 128. Duckworth-Rysiecki,G. and Taylor,A.M. (1985) Effects of (2005) Functional relationships of FANCC to homologous ionizing radiation on cells from Fanconi’s anemia patients. recombination, translesion synthesis, and BLM. EMBO J., Cancer Res., 45, 416–420. 24, 418–427. 129. Carreau,M., Alon,N., Bosnoyan-Collins,L., Joenje,H. and 148. Franchitto,A. and Pichierri,P. (2002) Bloom’s syndrome protein is Buchwald,M. (1999) Drug sensitivity spectra in Fanconi anemia required for correct relocalization of RAD50/MRE11/NBS1 lymphoblastoid cell lines of defined complementation groups. complex after replication fork arrest. J. Cell. Biol., 157, 19–30. Mutat. Res., 435, 103–109. 149. Zhang,R., Sengupta,S., Yang,Q., Linke,S.P., Yanaihara,N., 130. Tebbs,R.S., Hinz,J.M., Yamada,N.A., Wilson,J.B., Salazar,E.P., Bradsher,J., Blais,V., McGowan,C.H. and Harris,C.C. (2005) Thomas,C.B., Jones,I.M., Jones,N.J. and Thompson,L.H. (2005) BLM helicase facilitates Mus81 endonuclease activity in human New insights into the Fanconi anemia pathway from an isogenic cells. Cancer Res., 65, 2526–2531. FancG hamster CHO mutant. DNA Repair, 4, 11–22. 150. Hanada,K., Budzowska,M., Modesti,M., Maas,A., Wyman,C., 131. Taniguchi,T., Garcia-Higuera,I., Xu,B., Andreassen,P.R., Essers,J. and Kanaar,R. (2006) The structure-specific endonuclease Gregory,R.C., Kim,S.T., Lane,W.S., Kastan,M.B. and Mus81-Eme1 promotes conversion of interstrand DNA crosslinks D’Andrea,A.D. (2002) Convergence of the fanconi anemia and into double-strands breaks. EMBO J., 25, 4921–4932. ataxia telangiectasia signaling pathways. Cell, 109, 459–472. 151. Trowbridge,K., McKim,K., Brill,S.J. and Sekelsky,J. (2007) 132. Zhang,N., Liu,X., Li,L. and Legerski,R. (2007) Double-strand Synthetic lethality in the absence of the Drosophila MUS81 breaks induce homologous recombinational repair of interstrand endonuclease and the DmBlm helicase is associated with elevated cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and apoptosis. Genetics, 176, 1993–2001. the Fanconi anemia pathway. DNA Repair, 6, 1670–1678. 152. Martin,G.M. and Oshima,J. (2000) Lessons from human proger- 133. Hinz,J.M., Nham,P.B., Salazar,E.P. and Thompson,L.H. (2006) oid syndromes. Nature, 408, 263–266. The Fanconi anemia pathway limits the severity of mutagenesis. 153. Crabbe,L., Jauch,A., Naeger,C.M., Holtgreve-Grez,H. and DNA Repair, 5, 875–884. Karlseder,J. (2007) Telomere dysfunction as a cause of genomic 134. Lee,J.W., Harrigan,J., Opresko,P.L. and Bohr,V.A. (2005) instability in Werner syndrome. Proc. Natl Acad. Sci. USA, Pathways and functions of the Werner syndrome protein. Mech. 104, 2205–2210. Ageing Dev., 126, 79–86. 154. Goldstein,S. and Harley,C.B. (1979) In vitro studies of age- 135. Poot,M., Gollahon,K.A., Emond,M.J., Silber,J.R. and associated diseases. Fed. Proc., 38, 1862–1867. Rabinovitch,P.S. (2002) Werner syndrome diploid fibroblasts are 155. Du,X., Shen,J., Kugan,N., Furth,E.E., Lombard,D.B., Cheung,C., sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen: Pak,S., Luo,G., Pignolo,R.J. et al. (2004) Telomere shortening implications for the disease phenotype. FASEB J., 16, 757–758. exposes functions for the mouse Werner and Bloom syndrome 136. Poot,M., Yom,J.S., Whang,S.H., Kato,J.T., Gollahon,K.A. and genes. Mol. Cell. Biol., 24, 8437–8446. Rabinovitch,P.S. (2001) Werner syndrome cells are sensitive to 156. Sarkar,S., Davies,A.A., Ulrich,H.D. and McHugh,P.J. (2006) DNA cross-linking drugs. FASEB J., 15, 1224–1226. DNA interstrand crosslink repair during G1 involves nucleotide 137. Cheng,W.H., Kusumoto,R., Opresko,P.L., Sui,X., Huang,S., excision repair and DNA polymerase zeta. EMBO J., Nicolette,M.L., Paull,T.T., Campisi,J., Seidman,M. et al. (2006) 25, 1285–1294. Collaboration of Werner syndrome protein and BRCA1 in cellular 157. Bonatto,D., Revers,L.F., Brendel,M. and Henriques,J.A. (2005) responses to DNA interstrand cross-links. Nucleic Acids Res., The eukaryotic Pso2/Snm1/Artemis proteins and their function as 34, 2751–2760. genomic and cellular caretakers. Braz. J. Med. Biol. Res., 138. Zhang,N., Kaur,R., Lu,X., Shen,X., Li,L. and Legerski,R.J. 38, 321–334. (2005) The Pso4 mRNA splicing and DNA repair complex 158. Dronkert,M.L., de Wit,J., Boeve,M., Vasconcelos,M.L., van interacts with WRN for processing of DNA interstrand cross- Steeg,H., Tan,T.L., Hoeijmakers,J.H. and Kanaar,R. (2000) links. J. Biol. Chem., 280, 40559–40567. Disruption of mouse SNM1 causes increased sensitivity to the 7576 Nucleic Acids Research, 2007, Vol. 35, No. 22 DNA interstrand cross-linking agent mitomycin C. Mol. Cell. can restore the defect in mutagenesis of the pso4-1 mutant of Biol., 20, 4553–4561. S. cerevisiae. Mutat. Res., 314, 209–220. 159. Demuth,I., Digweed,M. and Concannon,P. (2004) Human 170. Morais Junior,M.A., Vicente,E.J., Brozmanova,J., Schenberg,A.C. SNM1B is required for normal cellular response to both DNA and Henriques,J.A. (1996) Further characterization of the yeast interstrand crosslink-inducing agents and ionizing radiation. pso4-1 mutant: interaction with rad51 and rad52 mutants after Oncogene, 23, 8611–8618. photoinduced psoralen lesions. Curr. Genet., 29, 211–218. 160. Ahkter,S., Richie,C.T., Zhang,N., Behringer,R.R., Zhu,C. and 171. Grillari,J., Hohenwarter,O., Grabherr,R.M. and Katinger,H. Legerski,R.J. (2005) Snm1-deficient mice exhibit accelerated (2000) Subtractive hybridization of mRNA from early passage and tumorigenesis and susceptibility to infection. Mol. Cell. Biol., senescent endothelial cells. Exp. Gerontol., 35, 187–197. 25, 10071–10078. 172. Voglauer,R., Chang,M.W., Dampier,B., Wieser,M., Baumann,K., 161. van Overbeek,M. and de Lange,T. (2006) Apollo, an Artemis- Sterovsky,T., Schreiber,M., Katinger,H. and Grillari,J. (2006) related nuclease, interacts with TRF2 and protects human SNEV overexpression extends the life span of human endothelial telomeres in S phase. Curr. Biol., 16, 1295–1302. cells. Exp. Cell Res., 312, 746–759. 162. Freibaum,B.D. and Counter,C.M. (2006) hSnm1B is a novel 173. Fortschegger,K., Wagner,B., Voglauer,R., Katinger,H., Sibilia,M. telomere-associated protein. J. Biol. Chem., 281, 15033–15036. and Grillari,J. (2007) Early embryonic lethality of mice lacking the 163. Lenain,C., Bauwens,S., Amiard,S., Brunori,M., Giraud-Panis,M.J. essential protein SNEV. Mol. Cell. Biol., 27, 3123–3130. and Gilson,E. (2006) The Apollo 5’ exonuclease functions together 174. Schraml,E., Voglauer,R., Fortschegger,K., Sibilia,M., Grillari,J. with TRF2 to protect telomeres from DNA repair. Curr. Biol., and Schauenstein,K. (in press) The expression of mSNEV, the 16, 1303–1310. murine homologue of human senescence evasion factor 164. Mahajan,K.N. and Mitchell,B.S. (2003) Role of human Pso4 in (SNEVPrp19/Pso4), is associated with the self-renewal capacity of mammalian DNA repair and association with terminal deoxynu- hematopoietic stem cells. Stem Cells Dev. cleotidyl transferase. Proc. Natl Acad. Sci. USA, 100, 10746–10751. 175. Ajuh,P., Kuster,B., Panov,K., Zomerdijk,J.C., Mann,M. and 165. Lu,X. and Legerski,R.J. (2007) The Prp19/Pso4 core complex Lamond,A.I. (2000) Functional analysis of the human CDC5L undergoes ubiquitylation and structural alterations in response to complex and identification of its components by mass spectro- DNA damage. Biochem. Biophys. Res. Commun., 354, 968–974. metry. EMBO J., 19, 6569–6581. 166. Grey,M., Dusterhoft,A., Henriques,J.A. and Brendel,M. (1996) 176. Hatakeyama,S., Yada,M., Matsumoto,M., Ishida,N. and Allelism of PSO4 and PRP19 links pre-mRNA processing with Nakayama,K.I. (2001) U-Box proteins as a new family of recombination and error-prone DNA repair in Saccharomyces ubiquitin-protein ligases. J. Biol. Chem., 276, 33111–33120. cerevisiae. Nucleic Acids Res., 24, 4009–4014. 177. Loscher,M., Fortschegger,K., Ritter,G., Wostry,M., 167. Grillari,J., Ajuh,P., Stadler,G., Loscher,M., Voglauer,R., Voglauer,R., Schmid,J.A., Watters,S., Rivett,A.J., Ajuh,P. et al. Ernst,W., Chusainow,J., Eisenhaber,F., Pokar,M. et al. (2005) (2005) Interaction of U-box E3 ligase SNEV with PSMB4, SNEV is an evolutionarily conserved splicing factor whose the beta7 subunit of the 20 S proteasome. Biochem. J., oligomerization is necessary for spliceosome assembly. Nucleic 388, 593–603. Acids Res., 33, 6868–6883. 178. Cho,S.Y., Shin,E.S., Park,P.J., Shin,D.W., Chang,H.K., Kim,D., 168. Henriques,J.A., Vicente,E.J., Leandro da Silva,K.V. and Lee,H.H., Lee,J.H., Kim,S.H. et al. (2006) Identification of mouse Schenberg,A.C. (1989) PSO4: a novel gene involved in error- Prp19p as a lipid droplet-associated protein and its possible prone repair in Saccharomyces cerevisiae. Mutat. Res., involvement in the biogenesis of lipid droplets. J. Biol. Chem., 218, 111–124. 20, 20. 169. Morais Junior,M.A., Brozmanova,J., Benfato,M.S., Duraj,J., 179. Kirkwood,T.B. (2005) Understanding the odd science of aging. Vlckova,V. and Henriques,J.A. (1994) The E. coli recA gene Cell, 120, 437–447. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nucleic Acids Research Oxford University Press

Contributions of DNA interstrand cross-links to aging of cells and organisms

Loading next page...
 
/lp/oxford-university-press/contributions-of-dna-interstrand-cross-links-to-aging-of-cells-and-JBK0fXKhKj

References (182)

Publisher
Oxford University Press
Copyright
© Published by Oxford University Press.
ISSN
0305-1048
eISSN
1362-4962
DOI
10.1093/nar/gkm1065
pmid
18083760
Publisher site
See Article on Publisher Site

Abstract

7566–7576 Nucleic Acids Research, 2007, Vol. 35, No. 22 Published online 14 December 2007 doi:10.1093/nar/gkm1065 SURVEY AND SUMMARY Contributions of DNA interstrand cross-links to aging of cells and organisms Johannes Grillari*, Hermann Katinger and Regina Voglauer Aging and Immortalization Research (A.I.R.), Institute of Applied Microbiology, Department of Biotechnology, BOKU – University of Natural Resources and Applied Life Sciences, Vienna, Muthgasse 18 1190 Vienna, Austria Received August 7, 2007; Revised and Accepted November 11, 2007 ABSTRACT transcription and prevents the use of information encoded by the complementary strand for repair. Thus, ICL Impaired DNA damage repair, especially deficient formation poses a major challenge for the cellular repair transcription-coupled nucleotide excision repair, systems, also reflected by the fact that estimated 40 ICLs leads to segmental progeroid syndromes in human in repair deficient mammalian cells are sufficient to induce patients as well as in rodent models. Furthermore, cell death (2). ICLs are considered to be mainly sensed DNA double-strand break signalling has been pin- during replication in S-phase, where they lead to collapse pointed as a key inducer of cellular senescence. of replication forks and DSBs, while little is known on transcription-coupled sensing and repair of ICLs. Several recent findings suggest that another Surprisingly, ICL repair seems also absent in mitochon- DNA repair pathway, interstrand cross-link (ICL) drial DNA (3). repair, might also contribute to cell and organism The mechanisms that lead to repair of ICLs are still not aging. Therefore, we summarize and discuss well understood in mammalian cells, but two major here that (i) systemic administration of anti-cancer pathways have been identified. The minor pathway chemotherapeutics, in many cases DNA cross- depends on ERCC1/XPF and translesion bypass by linking drugs, induces premature progeroid frailty Rev3 and is error-prone (4). The major pathway depends in long-term survivors; (ii) that ICL-inducing again on ERCC1/XPF and error-free homologous recom- 8-methoxy-psoralen/UVA phototherapy leads to bination repair (5). Excellent recent reviews summarizing signs of premature skin aging as prominent long- ICL repair are available for yeast (6,7) as well as for term side effect and (iii) that mutated factors involved mammalian cells (8–11). While other DNA damage repair pathways like in ICL repair like ERCC1/XPF, the Fanconi anaemia transcription-coupled nucleotide excision repair (NER) proteins, WRN and SNEV lead to reduced replicative have well-established links to aging of cells, tissues and life span in vitro and segmental progeroid syndromes organisms (12), it is not yet clear if and to what extent in vivo. However, since ICL-inducing drugs cause ICLs are involved in causing or contributing to progeroid damage different from ICL and since all currently functional decline. Therefore, we here summarize several known ICL repair factors work in more than one findings suggesting that exogenous exposure to ICL pathway, further work will be needed to dissect the inducing agents or endogenous ICL repair deficiencies actual contribution of ICL damage to aging. are associated with signs of premature aging. PREMATURE AGING AS SIDE EFFECT OF INTRODUCTION CHEMOTHERAPIES Each human cell has to repair the large numbers of ICL inducing agents used in tumour therapy different DNA damages encountered each day: around 50 000 single-strand breaks (SSB), 10 double-strand Most of our current knowledge on ICL repair derives breaks (DSB), 10 000 depurinations, 600 depyrimidations, from the use of ICL-inducing chemicals in biochemical or 2000 oxidative lesions, 5000 alkylating lesions and 10 genetic analysis of cells and cell lines on the one hand and interstrand cross-linking events (1). Although rare, DNA from their wide and successful use as anticancer interstrand cross-links (ICLs) are among the most deadly chemotherapeutics (13) on the other hand. Common to types of damage. The cross-linking of the two comple- all of these chemical compounds is their bifunctional mentary DNA strands prevents replication as well as character that allows them to react with both DNA *To whom correspondence should be addressed. Tel: +43 1 36006 6230; Fax: +43 1 3697615; Email: Johannes.grillari@boku.ac.at 2007 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Nucleic Acids Research, 2007, Vol. 35, No. 22 7567 strands. Although this is widely accepted as major skin changes, chronic fatigue and sexual dysfunction (32) cytotoxic effect, it should be noted that the individual as well as cardiovascular complications (33). We therefore ICL-inducing agents induce different specific steric DNA- propose to refer to this side effect of chemotherapies as adduct structures and that they generate other than ICL acquired premature progeroid syndrome (APPS) in damage like DNA monoadducts, intrastrand cross-links, analogy to the term premature progeroid syndromes for damage to lipids, RNA and proteins. Furthermore, hereditary diseases that resemble accelerated aging (34). different reactive intermediates can be formed by cellular While it is clear that a large proportion of cancer metabolism. For a detailed review, see Ref. 7. The most patients received ICL-inducing chemotherapeutics, the important substance classes used in cancer therapies are data so far have not been apportioned according to briefly summarized in the following. the drugs used. Thus, it is not yet clear if and how the Platinum compounds, the most famous of which is individual cross-linking agents differ in their long-term cisplatinum diammine dichloride II (CDDP) was one of effects and if and how they differ from chemotherapeu- the first chemotherapeutics originally identified as inhib- tics with other modes of action. itor of bacterial cell division (14). Since then it has been Similarly, it is not yet clear what causes APPS as a long- used to treat a wide range of different tumours (15,16) and term side effect. One possibility is the exhaustion of second-generation drugs are intensely worked on (17). The proliferative potential of stem and progenitor cells as well damage to the DNA mainly consists of intrastrand cross- as of normal differentiated cells by the cytotoxic drugs. links as well as around 5–8% ICL of total adducts (18,19), In this scenario, DNA damage induces cellular senescence which are responsible for the main cytotoxic effects (20). and/or apoptosis in damaged cells, forcing the surround- Bis(2-chloroethyl)methylamine (HN2) and other mem- ing undamaged cells to undergo repeated proliferation in bers of the nitrogen mustard family are as well widely used order to maintain tissue homoeostasis. This idea is as anti-cancer drugs (21). Again the majority of damage supported by several observations. consists of monoadducts to the DNA, however, the 1–5% Increased apoptosis as well as senescence after che- ICLs are responsible for the high cytotoxicity (22). motherapy has been reported in many studies (35), and Oligonucleotides conjugated to nitrogen mustards can be senescent cells accumulate in different tissues and organs used to introduce ICLs at specific sites in the genome (23). with age (36–38) and even in tumours (39). One trigger of One of the most used chemotherapeutics of the senescence is critically short, uncapped telomeres (40) and nitrosurea class is bis(2-chloroethyl)nitrosurea (BCNU, indeed accelerated telomere shortening has been observed carmustine), which decomposes in aqueous phase to so far in chemotherapy-treated patients versus age-matched uncharacterized reactive bifunctional molecules (24). The controls (41). Furthermore, deficiencies in DNA repair number of ICLs formed by this drug is estimated to be have been shown to impair haematopoietic stem cell around 8% of all adducts, and again this seems to be the function (42) or to even deplete the pool of haematopoie- main cytotoxic component (25). tic stem cells with age (43). Therefore, APPS might be Mitomycin C (MMC) is a quinine-containing antibiotic caused by a general decline of tissue regeneration and isolated from streptomycetes. Only its intermediates that repair capacity in consequence to chemotherapy. are formed after several intracellular metabolic activation steps generate ICLs, which make up 5–14% of all adducts (26). The ICLs mainly affect dCpG sequences in the minor PSORALEN/UVA-INDUCED ICLs AND groove of DNA. A recent derivative, aziridinomitosene 4, PREMATURE SKIN AGING has been shown to have very high ICL-forming activity Psoralens belong to the furocoumarins, bifunctional without prior metabolization (27). Besides forming agents that form ICLs as well as thymine monoadducts adducts, MMC also induces production of reactive upon UVA activation and are among the most potent oxygen species (ROS), which also contributes to its interstrand cross-linking agents. Upon selection of differ- cytotoxicity (28). ent wavelengths up to 40% of the monoadducts can be Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) are a family converted to ICLs. Psoralen cytotoxicity is clearly linked of DNA interactive anti-tumour antibiotics derived from to ICL-forming activity, since exposure of cells to various Streptomyces species. One of the most promising psoralens with UV wavelengths that do not induce ICLs derivatives thereof is SJG-136, which displays a 440-fold or monofunctional psoralens not able to form ICLs are higher ICL formation activity than the nitrogen mustards markedly less toxic (44). (29,30). ICLs are targeted to the minor groove of the For studying response to and repair of specific ICLs, DNA even in a non-reductive environment (31). targeted single ICLs can be introduced into the genome using either oligonucleotides forming triplex DNA at the Early onset of progeroid frailty after chemotherapy complementary sites or peptide nucleic acids conjugated to Only now, after several decades of using ICL-inducing dimeric bis-psoralen (45,46). Furthermore, a digoxigenin- drugs in chemotherapy against cancer, sufficient patients 4,5’,8-trimethylpsoralen conjugate enables visualization of with more than 10 years survival are available for studying ICLs in cultured cells (47). long-term side effects. Several years after the initial The clinical conditions for which 8-methoxy-psoralen/ treatment, patients suffer from a variety of problems that UVA treatment (PUVA) has been widely and successfully usually occur later in life like decline of cognitive functions, used over decades are skin diseases like psoriasis, vitiligo visual deterioration, musculoskeletal decline, osteoporosis, and mycosis fungoides. The therapeutic effect depends on 7568 Nucleic Acids Research, 2007, Vol. 35, No. 22 formation of ICLs the massive formation of which has biosynthesis, and oxidative burst of immune cells. been observed in treated tissues (48). One prominent side Extrinsic sources like UV light, or heavy metal ions effect of repeated PUVA treatment is premature aging of contribute to ROS production as well (67). Free radicals have been postulated to be a major cause the skin (49–51). As a model to study the underlying mechanisms, human of aging in the ‘free radical theory of aging’ (68) and there is little doubt that ROS contribute to deterioration of cell fibroblasts and keratinoycytes have been subjected to (69) and organ function, e.g. brain (70), kidney (71,72), PUVA treatment. These studies suggest that premature liver (73) or heart (74). Increased formation of ROS (75), skin aging might be due to induction of a cellular lipid peroxidation products and reactive aldehydic mole- senescence programme triggered specifically by ICL cules (one of which would be malondialdehyde) has indeed formation (51–54) resembling a combined DNA damage been observed during aging (76–78). In addition, lipid and stress-induced phenotype at least at the transcrip- peroxidation products have been suggested as one tional level (55). parameter in a possible set of clinical aging markers (79). PUVA-induced senescence is signalled by ATR (56), However, direct evidence for an increase of malondial- whose importance for ICL repair is emphasized by data dehyde and in consequence malondialdehyde-ICLs has from Saccharomyces cerevisiae. Yeast ATR’s homologue not yet been provided, since the age-comparative studies Mec1 is activated by the heterotrimeric Rad17– so far were based on quantification of the bulk of reactive Mec3–Ddc1 complex (57). Surprisingly, MEC3 has aldehydes only, e.g. using thiobarbituric acid reactive recently been identified to be allelic to Pso9, mutations substances (TBARS) assay. in which render yeast cells sensitive to PUVA (58). Might there also be a difference between fast induction Furthermore, the human Rad17–Mec3–Ddc1 homologue of ICLs versus slow gradual increase as expected during called Rad9/Rad1/Hus1 (911) complex localizes to telo- aging due to gradual ROS increase (80,81)? Two studies meres and modulates telomere length and telomerase suggest that slow accumulation of DNA damage indeed activity (59). results in higher cytotoxicity than short-term high-dose While in the short-term cell cycle arrest is telomere- exposure. In the first study, HCT 116 cells were treated for independent, after 28 days after recovery from PUVA 24 h with low doses of the ICL-inducing agent SJG-136, treatment, senescence is still maintained with DNA leading to gradual formation of ICLs, and limited damage foci persisting mainly at telomeres as detected p21-induced cell cycle arrest. This resulted in significantly by co-staining of g-H2AX with telomere-specific fluores- higher cytotoxicity than a 1 h treatment with high doses of cence in situ hybridization. In contrast, intrachromosomal SJG-136 that caused full DNA damage response, although DNA damage has largely been repaired during the dose and time of treatment were carefully chosen to yield recovery (56). It is not clear why the damage foci persist similar final levels of ICLs within the cells (82). Similarly, at the telomeres and what might be the nature of this in the second study, low doses versus high doses of the damage. In this regard, it is of interest that telomeric DNA-damaging agents, hydroxyurea and UV were t-loops are efficiently maintained after psoralen cross- compared in three cell lines partially deficient in different linking (60), and that telomeric sequence contains the TA components of ATR-mediated signalling. Again, low basepairing within the TTAGGG repeats that are prime doses were found to cause significantly more cell death targets of 8-methoxypsoralen (61). This suggests that the accompanied with slow/insufficient activation of damage telomeres might be exquisitely susceptible to ICLs and signalling and repair (83). that PUVA treatment might cause more ICL per kilobase DNA at the telomere than within genomic sequences, and/ or that ICL repair is less efficient at the telomeres. ICL REPAIR DEFICIENCY CONTRIBUTES TO Besides senescence, apoptosis might be involved in the SIGNS OF ACCELERATED AGING reduction of the proliferative capacity of skin cells, since in vitro and in vivo PUVA has been shown to induce Although ICL repair is still not fully understood in higher apoptosis in epidermal cells via p53 and Fas ligand (62). eukaryotic cells, several central players have been identi- fied during the last years including, ERCC1/XPF, the Fanconi anaemia proteins, but also the RecQ helicases DOES ENDOGENOUS FORMATION OF ICLs WRN and BLM. Patients and corresponding animal INCREASE WITH AGE? models with mutations in these factors display various grades of segmental progeroid syndromes. In addition, So far, ICL formation by exogenous sources is undoubted, other factors contributing to ICL repair like SNM1/hPso2 but how do ICLs arise spontaneously within cells and or SNEV have been connected to cellular aging and tissues? One of the few currently known endogenously telomere biology. However, it has to be kept in mind that generated molecules causing ICLs is the bifunctional lipid all of the ICL factors described so far work in more than peroxidation product malondialdehyde. Various studies one DNA repair pathway or exert more than one have identified specific cross-link structures by malondial- function. dehyde with DNA in vitro (63) as well as in vivo in a variety of human tissues (64–66). ERCC1/XPF ROS necessary for peroxidation of lipids to malondial- dehyde arise from intrinsic cellular pathways, above all ERCC1/XPF is a structure-specific heterodimeric endo- from cell respiration, but also during prostaglandin nuclease essential in NER, but also during ICL repair. Nucleic Acids Research, 2007, Vol. 35, No. 22 7569 Incisions near the ICL site that ‘unhook’ the cross-linked IGF1 signalling was found in livers of ERCC1-deficient oligonucleotide specifically depend on ERCC1/XPF mice (96). Similar suppression of the IGF1/GH axis is seen (84,85). Mutations in both of its subunits have been after exposure of wild-type mice to chronic genotoxic found to cause segmental progeroid syndromes in stress using MMC (96). This would suggest that high humans. Similarly, mouse models deficient in ERCC1 levels of ICL damage provide a feedback signal to (86,87) as well as in XPF (88) show a congruent severe suppress growth at the organism level, probably in order progeroid phenotype that is quite distinct in severity from to allocate more energy to cellular maintenance and repair –/– most other mouse models deficient in NER only. ERCC in order to prolong the life span (96). Absence of IGF1 mice show ataxia, kyphosis, osteopenia, weight loss, skin suppression in XPA or Cockayne syndrome B-deficient atrophy, sarcopenia and hepatocellular polyploidization mice would argue against ERCC1’s NER function as (89) and the fibroblasts are exquisitely sensitive to cross- reason for developing progeroid phenotypes. It would be linking agents but also to UV light (87). interesting to test if impaired IGF1-signalling back- Recently, the first patient deficient in ERCC1 has been grounds [e.g. in Ames or Snell dwarf mice (102)] would identified, displaying a severe disease phenotype of additionally reduce the life span and increase severity or cerebro-oculo-facio-skeletal syndrome that also in part accelerate the appearance of progeroid symptoms resembles premature aging and resulted in early death observed with ICL repair deficiency. (90). In contrast to the knockout mouse model, cells of Further contributions to a premature aging phenotype this patient, showed only intermediate sensitivity to UV might derive from increased apoptosis as observed in liver –/– and MMC treatment, comparable to other NER-deficient tissue (103), decreased replicative potential of ERCC1 cells (90). embryonic fibroblasts (87) as well as depletion of This finding suggests that XPF/ERCC1 functions hematopoietic stem cells, which again is not observed in besides NER repair might confer the severity of the XPA mutant mice (104). mutation. Indeed, XPF/ERCC1 is required for meiotic An experimental setting that might allow for addressing and mitotic homologous recombination in mouse and fly ERCC1 deficiency in humans possibly arises from the (91,92) and also implicated in telomere processing, finding that ERCC1 is transcriptionally repressed by responsible for removing the 3’ overhang of uncapped fludarabine treatment (105,106), and increases ICLs telomeres (93). Surprisingly, the endonuclease function synergistically with cisplatin or oxaliplatin (107,108). required for both ICL and NER is separated from the Fludarabine is a chemotherapeutic drug mainly used telomere processing function of XPF, since a point against haematological malignancies (109). It would be of mutation that abrogates DNA repair does not interfere interest to analyse if this drug also leads to APPS in long- with 3’ overhang removal in cell culture experiments (94). term survivors. Furthermore, NER and ICL repair functions of XPF might be separable as well (95). This is consistent with the clinical appearance of the FA pathway currently known XPF mutations. Most of them result in FA is a disorder showing developmental and bone marrow mild forms of xeroderma pigmentosa (XP), a cancer-prone defects, as well as cancer predisposition (110). This rare syndrome characterized by high UV sensitivity. In hereditary disease is caused by mutations in one of contrast, one patient with a dramatic progeroid phenotype currently 13 proteins constituting 13 complementation has been identified bearing a novel mutation in XPF groups [FANCA, B, C, E, F, G, L and M forming a core (R153P9) interfering with formation of ERCC1 hetero- complex, D1, D2(BRCA2), H, I, J]. FAAP24 has recently dimers (96). Primary fibroblasts of this patient are much been proven as an additional FA complex member, more sensitive to ICL-inducing MMC as compared to although it has not been found mutated in FA patients XPA-derived cells, while they are only similarly sensitive yet (111). Recent progress in understanding the functions to UV irradiation (96). This finding would also support a of FA proteins and the ‘FA pathway’ has been reviewed in specific role of deficient ICL repair distinct from NER detail (9–11,112,113). deficiency in accelerating the aging process. Clearly, Although not being ranked among the segmental further work is required for dissecting the contributions progeroid syndromes in the initial listing by George of different mutations in XPF and ERCC1 in the observed Martin (34), there still seems to be a segmental premature progeroid features. It would for example be of high aging component in FA. This consists of progressive bone interest, to complement XPF-deficient mice with con- marrow failure, squamous cell carcinomas of the oral structs harbouring the various mutants, to see if and to cavity and genital area much earlier in life than in normal what extent ICL, NER, and dysfunctional telomere individuals, impaired gametogenesis and premature repro- processing of XPF contribute to their progeroid ductive aging. Additionally, >80% of FA patients are phenotype. prematurely affected by endocrine abnormalities including A completely different and much unexpected link hyperinsulinaemia, hypothyroidism and growth hormone between ERRC1 deficiency and aging has been discovered deficiency, all of which are normally associated with recently. Suppression of IGF1 signalling is one of the very advanced age (114). Decline of growth hormone is of note, few conserved mechanisms that prolongs life span in a wide range of model organisms from S. cerevisiae (97), since this leads to less IGF signalling similar to ERCC1/ Caenorhabditis elegans (98), Dorsophila melanogaster (99), XPF deficiency, supporting the idea of a general switch and mouse (100,101). Surprisingly, this suppression of from growth to repair upon (ICL?) damage. 7570 Nucleic Acids Research, 2007, Vol. 35, No. 22 Furthermore, cells of FA patients show signs of WRN activity might be necessary at different points of accelerated cellular senescence. PBMCs have accelerated ICL repair. It interacts with the SNEV-complex (see below) in early steps of repairing single psoralen ICLs individual annual telomere-shortening rates in vivo in vitro (138), while in the later HR repair step it interacts (115–117) while fibroblasts derived from FA patients with a complex containing Rad51, ATR, Rad54 and show accelerated telomere shortening in vitro (118), Rad54B (139) localizing to stalled replication forks (140). consistent with a reduced replicative life span and earlier entry into cellular senescence (119,120). This accelerated Another protein–protein interaction linking WRN to ICL telomere erosion, however, is not due to faster replicative repair derives from yeast, where its homologue sgs1 shortening, but to increased telomere breakage (121). interacts with Pso5/rad16 (141), involved in ICL repair and global NER (142). Together with an increase in apoptosis of haematopoietic A second RecQ helicase family member, which also stem cells (122,123), this might also contribute to the physically and functionally interacts with WRN (143), progressive bone marrow failure in patients (124) as well is BLM. Fibroblasts derived from Bloom’s syndrome as in knockout mouse models (125–127). patients show sensitivity to MMC treatment (144) To what extent are the FA proteins involved in ICL and to cisplatin (145). Both helicases have also been repair? While indeed hypersensitivity against ICLs by found to interact with members of the FA complex MMC and diepoxybutane is a common hallmark of all subunits and with HR factors (137,146–148). FA cells and used as standard diagnosis of FA, there is a Furthermore, FA core complex assembly is necessary broad spectrum of additional sensitivities against geno- for BLM phosphorylation and localization to nuclear foci toxic damage including g-irradiation, bleomycin, UV and upon ICLs (144). The unwinding activity of BLM also methyl methane sulphate depending on the cell type of the enhances Mus81 endonuclease activity (149), which same patient (128) as well as on the complementation converts ICLs to DSBs (150). Genetic interaction group (129). For example, FANCG null Chinese hamster between Mus81 and BLM homologues in D. melanogaster ovary (CHO) cells are similarly sensitive against mono- further supports their function in a common alkylating agents as against ICL-inducing agents (130). pathway (151). Furthermore, monoubiquitination of FANCD2, a crucial Mutations in both helicases cause prominent segmental step in activation of the ‘FA protein pathway’ is also progeroid syndromes. WRN mutations are the cause of induced by chemically blocking replication forks (131). Werner syndrome (152). High genomic instability is These findings led to the proposal that the FA proteins— observed in cells of Werner syndrome patients due to rather than being specifically necessary for ICL—might massive loss of telomeric sequences during replication act more globally on stabilizing collapsed replication forks (153), also leading to a reduced replicative life span in vitro that do not exclusively arise due to ICL (11). Collapse (154). of replication forks leads to formation of DSB, which Similarly, Bloom syndrome, is prominently ranked have recently been suggested to be a prerequisite for among the segmental progeroid disorders (152) and HR-dependent repair of ICL (132). The FA proteins BLM, like WRN, is necessary for telomere functionality might prevent the DSBs from being repaired by non- (155). Again, a clear attribution of accelerated aging to homologous end joining by keeping the broken strands in ICLs is not possible in the background of WRN and BLM close proximity. Thus, the FA pathway might largely mutations, since their functions are not limited to ICL counteract genomic instabilities by favouring base sub- repair. stitutions and small deletions over larger deletions and chromosomal rearrangements (10,11,133). Still, FA pro- hPSO2 (SNM1) teins are needed together with Msh2, ERCC1/XPF and Rev3 in HR-dependent repair of single psoralen-induced The nomenclature of the Pso genes is derived from ICLs (132). yeast cells displaying sensitivity to 8-methoxy-psoralen/ Further work is necessary to dissect if and to what UVA treatment (142). Yeast Pso2 is involved in trans- extent reduced ICL repair, failed stabilization of replica- lesion synthesis repair of ICL during G1 (156). The five tion forks or other DNA damage contribute to the homologues in humans are SNM1, SNM1B/Apollo, and progeroid symptoms in FA. To further complicate SNM1C/Artemis, ELAC2 and CPSF73, all of them things, FA cells also show elevated ROS levels and containing a b-CASP/metallo-b-lactamase domain (157). increased sensitivity against ROS (123). Therefore, it Sensitivity to ICL has been established for SNM1 in cannot be excluded that ROS cause or additively knockout mice (158) and for SNM1B/Apollo in human contribute to premature aging in FA patients. cells by siRNA-mediated knockdown (159). SNM1 knockout mice-derived cells show MMC sensitivity (158) as well as increased tumour incidence and immune BLM and WRN helicases deficiency (160). However, only weak resemblance to Besides its function in base excision DNA repair (134), the aging is observed in these mice. RecQ helicase member WRN has also been implicated in The second homologue, SNM1B/Apollo interacts with ICL repair. Cells from Werner syndrome patients show TRF2 and thus localizes to telomeres (161–163). Its sensitivity to ICL-inducing drugs (135,136) and WRN knockdown in human fibroblasts leads to rapid loss of helicase activity has been shown necessary for repair of telomeric sequences, accelerated entry into replicative PUVA-induced ICLs (137). senescence and formation of g-H2AX DNA damage Nucleic Acids Research, 2007, Vol. 35, No. 22 7571 Figure 1. Overview of a proposed contribution of DNA interstrand cross-links (ICLs) to aging: increased formation of ICLs leads to acquired premature progeroid syndrome (APPS) by exhaustion of replicative potential of stem and progenitor as well as normal cells, while suppression of IGF1 signalling redirects energy from growth to repair and maintenance. foci. If SNM1B/Apollo mutations also affect organismal (178), again makes it very difficult to dissect if its aging has not been analysed yet. ICL repair function is connected to cellular aging. If SNEV haploinsufficient mice show premature progeroid symptoms and reduced life span like the SAMP8 mice is SNEV (hPSO4) currently under investigation. The SNEV core complex consisting of CDC5L, SNEV (hPSO4, hNMP200, hPRP19), SPF27 (BCAS1) and CONCLUSIONS PLRG1 together with WRN helicase is essential in early steps of ICL repair in vitro using single psoralen Three different types of conditions that induce increased cross-linked plasmids as substrate for fractionated HeLa levels of ICLs have been summarized here: chemother- nuclear extracts (138). Furthermore SNEV binds dsDNA apeutic treatment of cancer using ICL-inducing drugs, and might accumulate upon MMC, but also upon PUVA treatment of skin diseases and increase of g-irradiation and bleomycin treatment in cell cultures endogenously formed ICLs by impaired ICL repair. All (164), while it clearly is ubiquitinated upon MMC and of these conditions lead to more or less pronounced methyl-methan-sulphonate treatment (165). progeroid features, clearly indicating that DNA damage is SNEV’s involvement in DNA repair is consistent with among the driving forces of aging and age-associated the role of its yeast orthologue Pso4 (Prp19) (166,167), pathologies. Although it seems clear that ICLs contribute where the temperature-sensitive mutant strain pso4-1 to aging-like loss of functions, their specific contribution displays a pleiotropic phenotype that includes sensitivity remains unknown due to the facts that all ICL-inducing to 8-methoxy-psoralen/UVA treatment (168). In yeast, drugs cause additional damage other than ICL and all Pso4 has been assigned to epistasis groups rad6 and rad52, currently known proteins involved in ICL repair have emphasizing its pleiotropic nature (169,170). other functions as well. Similarly, several other factors How is SNEV connected to aging? It was originally conferring hypersensitivity to ICL-inducing agents have isolated as mRNA that decreases during replicative not been linked to aging yet, e.g. the other Pso proteins senescence of endothelial cells (171), while upon over- like Pso1/Rev3 or the Rad51 paralogues XRCC2, XRCC3 expression it extends the replicative life span and reduces and Rad51C. basal apoptotic levels (172). Targeted disruption of SNEV How is ICL damage translated to aging of organisms? is early embryonic lethal, but haploinsufficiency causes A major contributor might be the exhaustion of replicative mouse embryonic fibroblasts to enter early into replicative potential of stem, progenitor and normal cells due to senescence in vitro (173). In addition, we recently found a increased apoptosis and senescence upon damage, while decrease in the self-renewal capacity of haematopoietic suppression of the IGF1 signalling might be a counter- +/– stem cells derived from SNEV mice as well as from active measure aimed at funnelling energy to repair and senescence accelerated SAMP8 mice. Haematopoietic maintenance of the damaged cells as summarized in our stem cells from both have significantly reduced SNEV model (Figure 1). levels as compared to wild-type or long-lived SAMR1 While our model is consistent with the idea that aging is controls (174). This further supports a link between DNA accelerated by stochastic damage but counteracted by repair, low replicative life span and the regenerative genetically programmed repair (179), it is so far only capacity of stem cells. based on induction of premature progeroid syndromes However, the multiplicity of SNEV’s functions as an and shortening of life span. An important unanswered essential pre-mRNA splicing factor (167,175), as ubiquitin question therefore is if reduced ICL induction or E3 ligase (176,177) and lipid droplet-binding protein improved ICL repair, e.g. by overexpression of ICL 7572 Nucleic Acids Research, 2007, Vol. 35, No. 22 indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] repair factors would be able to prolong the life and health (KP1019 or FFC14A). J. Inorg. Biochem., 100, 891–904. span of organisms. 18. Brabec,V. and Leng,M. (1993) DNA interstrand cross-links of trans-diamminedichloroplatinum(II) are preferentially formed between guanine and complementary cytosine residues. Proc. Natl Acad. Sci. USA, 90, 5345–5349. ACKNOWLEDGEMENTS 19. Jones,J.C., Zhen,W.P., Reed,E., Parker,R.J., Sancar,A. and This work was supported by grant NRN-S09306 of the Bohr,V.A. (1991) Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster Austrian Science Fund (FWF) and by Polymun Scientific ovary cells. J. Biol. Chem., 266, 7101–7107. GmbH, Vienna, Austria. We especially want to acknowl- 20. Roberts,J.J. and Friedlos,F. (1987) Quantitative estimation of edge our reviewers for generously providing helpful cisplatin-induced DNA interstrand cross-links and their repair in comments on this manuscript. Funding to pay the Open mammalian cells: relationship to toxicity. Pharmacol. Ther., 34, 215–246. Access publication charges for this article was provided 21. Balcome,S., Park,S., Quirk Dorr,D.R., Hafner,L., Phillips,L. and by Austrian Science Fund (FWF). Tretyakova,N. (2004) Adenine-containing DNA–DNA cross- links of antitumor nitrogen mustards. Chem. Res. Toxicol., Conflict of interest statement. None declared. 17, 950–962. 22. Rink,S.M. and Hopkins,P.B. (1995) A mechlorethamine-induced DNA interstrand cross-link bends duplex DNA. Biochemistry, 34, 1439–1445. REFERENCES 23. Singer,M.J., Podyminogin,M.A., Metcalf,M.A., Reed,M.W., 1. Lindahl,T. and Barnes,D.E. (2000) Repair of endogenous DNA Brown,D.A., Gamper,H.B., Meyer,R.B. and Wydro,R.M. (1999) damage. Cold Spring Harb. Symp. Quant. Biol., 65, 127–133. Targeted mutagenesis of DNA with alkylating RecA assisted 2. Akkari,Y.M., Bateman,R.L., Reifsteck,C.A., Olson,S.B. and oligonucleotides. Nucleic Acids Res., 27, e38. Grompe,M. (2000) DNA replication is required to elicit cellular 24. Colvin,M., Cowens,J.W., Brundrett,R.B., Kramer,B.S. and responses to psoralen-induced DNA interstrand cross-links. Ludlum,D.B. (1974) Decomposition of BCNU (1,3-bis Mol. Cell. Biol., 20, 8283–8289. (2-chloroethyl)-1-nitrosourea) in aqueous solution. Biochem. 3. Cullinane,C. and Bohr,V.A. (1998) DNA interstrand cross-links Biophys. Res. Commun., 60, 515–520. induced by psoralen are not repaired in mammalian mitochondria. 25. Wiencke,J.K. and Wiemels,J. (1995) Genotoxicity of 1,3-bis Cancer Res., 58, 1400–1404. (2-chloroethyl)-1-nitrosourea (BCNU). Mutat. Res., 339, 91–119. 4. Shen,X., Jun,S., O’Neal,L.E., Sonoda,E., Bemark,M., Sale,J.E. and 26. Seow,H.A., Penketh,P.G., Baumann,R.P. and Sartorelli,A.C. (2004) Li,L. (2006) REV3 and REV1 play major roles in recombination- Bioactivation and resistance to mitomycin C. Methods Enzymol., independent repair of DNA interstrand cross-links mediated by 382, 221–233. monoubiquitinated proliferating cell nuclear antigen (PCNA). 27. Rink,S.M., Warner,D.L., Klapars,A. and Vedejs,E. (2005) J. Biol. Chem., 281, 13869–13872. Sequence-specific DNA interstrand cross-linking by an aziridino- 5. Collins,A.R. (1993) Mutant rodent cell lines sensitive to ultraviolet mitosene in the absence of exogenous reductant. Biochemistry, light, ionizing radiation and cross-linking agents: a comprehensive 44, 13981–13986. survey of genetic and biochemical characteristics. Mutat. Res., 28. Pagano,G. (2002) Redox-modulated xenobiotic action and 293, 99–118. ROS formation: a mirror or a window? Hum. Exp. Toxicol., 6. Dronkert,M.L. and Kanaar,R. (2001) Repair of DNA interstrand 21, 77–81. cross-links. Mutat. Res., 486, 217–247. 29. Gregson,S.J., Howard,P.W., Gullick,D.R., Hamaguchi,A., 7. Lehoczky,P., McHugh,P.J. and Chovanec,M. (2007) DNA inter- Corcoran,K.E., Brooks,N.A., Hartley,J.A., Jenkins,T.C., Patel,S. strand cross-link repair in Saccharomyces cerevisiae. FEMS et al. (2004) Linker length modulates DNA cross-linking reactivity Microbiol. Rev., 31, 109–133. and cytotoxic potency of C8/C8’ ether-linked C2-exo-unsaturated 8. Niedernhofer,L.J., Lalai,A.S. and Hoeijmakers,J.H. (2005) Fanconi pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers. J. Med. Chem., anemia (cross)linked to DNA repair. Cell, 123, 1191–1198. 47, 1161–1174. 9. Levitus,M., Joenje,H. and de Winter,J.P. (2006) The Fanconi 30. Gregson,S.J., Howard,P.W., Hartley,J.A., Brooks,N.A., anemia pathway of genomic maintenance. Cell Oncol., 28, 3–29. Adams,L.J., Jenkins,T.C., Kelland,L.R. and Thurston,D.E. (2001) 10. Kennedy,R.D. and D’Andrea,A.D. (2005) The Fanconi anemia/ Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine BRCA pathway: new faces in the crowd. Genes Dev., 19, 2925–2940. DNA-interactive agent with highly efficient cross-linking ability and 11. Thompson,L.H., Hinz,J.M., Yamada,N.A. and Jones,N.J. (2005) potent cytotoxicity. J. Med. Chem., 44, 737–748. How Fanconi anemia proteins promote the four Rs: replication, 31. Martin,C., Ellis,T., McGurk,C.J., Jenkins,T.C., Hartley,J.A., recombination, repair, and recovery. Environ. Mol. Mutagen., Waring,M.J. and Thurston,D.E. (2005) Sequence-selective interac- 45, 128–142. tion of the minor-groove interstrand cross-linking agent SJG-136 12. Mitchell,J.R., Hoeijmakers,J.H. and Niedernhofer,L.J. (2003) with naked and cellular DNA: footprinting and enzyme inhibition Divide and conquer: nucleotide excision repair battles cancer and studies. Biochemistry, 44, 4135–4147. ageing. Curr. Opin. Cell. Biol., 15, 232–240. 32. Maccormick,R.E. (2006) Possible acceleration of aging by adjuvant 13. McHugh,P.J., Spanswick,V.J. and Hartley,J.A. (2001) Repair of chemotherapy: a cause of early onset frailty? Med. Hypotheses, DNA interstrand crosslinks: molecular mechanisms and clinical 67, 212–215. relevance. Lancet Oncol., 2, 483–490. 33. Meinardi,M.T., Gietema,J.A., van Veldhuisen,D.J., van der 14. Rosenberg,B., Vancamp,L. and Krigas,T. (1965) Inhibition of cell Graaf,W.T., de Vries,E.G. and Sleijfer,D.T. (2000) Long-term division in Escherichia coli by electrolysis products from a platinum chemotherapy-related cardiovascular morbidity. Cancer Treat. Rev., electrode. Nature, 205, 698–699. 26, 429–447. 15. Boulikas,T. and Vougiouka,M. (2004) Recent clinical trials using 34. Martin,G.M. (1978) Genetic syndromes in man with potential cisplatin, carboplatin and their combination chemotherapy drugs relevance to the pathobiology of aging. Birth Defects Orig. Artic. (review). Oncol. Rep., 11, 559–595. Ser., 14, 5–39. 16. Galanski,M., Jakupec,M.A. and Keppler,B.K. (2005) Update of the 35. Roninson,I.B. (2002) Tumor senescence as a determinant of drug preclinical situation of anticancer platinum complexes: novel design response in vivo. Drug Resist. Updat., 5, 204–208. strategies and innovative analytical approaches. Curr. Med. Chem., 36. Herbig,U., Ferreira,M., Condel,L., Carey,D. and Sedivy,J.M. (2006) 12, 2075–2094. Cellular senescence in aging primates. Science, 311, 1257. 17. Hartinger,C.G., Zorbas-Seifried,S., Jakupec,M.A., Kynast,B., 37. Erusalimsky,J.D. and Kurz,D.J. (2005) Cellular senescence in vivo: Zorbas,H. and Keppler,B.K. (2006) From bench to bedside – Its relevance in ageing and cardiovascular disease. Exp. Gerontol., preclinical and early clinical development of the anticancer agent 40, 634–642. Nucleic Acids Research, 2007, Vol. 35, No. 22 7573 38. Halloran,P.F. and Melk,A. (2001) Renal senescence, cellular pso9-1 of Saccharomyces cerevisiae contains a mutant allele of the senescence, and their relevance to nephrology and transplantation. DNA damage checkpoint gene MEC3. DNA Repair, 5, 163–171. Adv. Nephrol. Necker Hosp., 31, 273–283. 59. Francia,S., Weiss,R.S., Hande,M.P., Freire,R. and d’Adda di 39. Van Nguyen,T., Puebla-Osorio,N., Pang,H., Dujka,M.E. and Fagagna,F. (2006) Telomere and telomerase modulation by the Zhu,C. (2007) DNA damage-induced cellular senescence is sufficient mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex. to suppress tumorigenesis: a mouse model. J. Exp. Med., Curr. Biol., 16, 1551–1558. 204, 1453–1461. 60. Griffith,J.D., Comeau,L., Rosenfield,S., Stansel,R.M., Bianchi,A., 40. de Lange,T. (2005) Shelterin: the protein complex that shapes and Moss,H. and de Lange,T. (1999) Mammalian telomeres end in a safeguards human telomeres. Genes Dev., 19, 2100–2110. large duplex loop. Cell, 97, 503–514. 41. Beeharry,N. and Broccoli,D. (2005) Telomere dynamics in response 61. Van Houten,B., Gamper,H., Hearst,J.E. and Sancar,A. (1986) to chemotherapy. Curr. Mol. Med., 5, 187–196. Construction of DNA substrates modified with psoralen at a unique 42. Rossi,D.J., Bryder,D., Seita,J., Nussenzweig,A., Hoeijmakers,J. and site and study of the action mechanism of ABC excinuclease on Weissman,I.L. (2007) Deficiencies in DNA damage repair limit the these uniformly modified substrates. J. Biol. Chem., function of haematopoietic stem cells with age. Nature, 261, 14135–14141. 447, 725–729. 62. Santamaria,A.B., Davis,D.W., Nghiem,D.X., McConkey,D.J., 43. Nijnik,A., Woodbine,L., Marchetti,C., Dawson,S., Lambe,T., Ullrich,S.E., Kapoor,M., Lozano,G. and Ananthaswamy,H.N. Liu,C., Rodrigues,N.P., Crockford,T.L., Cabuy,E. et al. (2007) (2002) p53 and Fas ligand are required for psoralen and DNA repair is limiting for haematopoietic stem cells during ageing. UVA-induced apoptosis in mouse epidermal cells. Cell Death Nature, 447, 686–690. Differ., 9, 549–560. 44. Bethea,D., Fullmer,B., Syed,S., Seltzer,G., Tiano,J., Rischko,C., 63. Marnett,L.J. (2000) Oxyradicals and DNA damage. Carcinogenesis, Gillespie,L., Brown,D. and Gasparro,F.P. (1999) Psoralen photo- 21, 361–370. biology and photochemotherapy: 50 years of science and medicine. 64. Kadlubar,F.F., Anderson,K.E., Haussermann,S., Lang,N.P., J. Dermatol. Sci., 19, 78–88. Barone,G.W., Thompson,P.A., MacLeod,S.L., Chou,M.W., 45. Kim,K.H., Fan,X.J. and Nielsen,P.E. (2007) Efficient sequence- Mikhailova,M. et al. (1998) Comparison of DNA adduct levels directed psoralen targeting using pseudocomplementary Peptide associated with oxidative stress in human pancreas. Mutat. Res., nucleic acids. Bioconjug. Chem., 18, 567–572. 405, 125–133. 46. Kim,K.H., Nielsen,P.E. and Glazer,P.M. (2006) Site-specific gene 65. Sharma,R.A., Gescher,A., Plastaras,J.P., Leuratti,C., Singh,R., modification by PNAs conjugated to psoralen. Biochemistry, Gallacher-Horley,B., Offord,E., Marnett,L.J., Steward,W.P. et al. 45, 314–323. (2001) Cyclooxygenase-2, malondialdehyde and pyrimidopurinone 47. Thazhathveetil,A.K., Liu,S.T., Indig,F.E. and Seidman,M.M. (2007) adducts of deoxyguanosine in human colon cells. Carcinogenesis, Psoralen conjugates for visualization of genomic interstrand cross- 22, 1557–1560. links localized by laser photoactivation. Bioconjug. Chem., 66. Niedernhofer,L.J., Daniels,J.S., Rouzer,C.A., Greene,R.E. and 18, 431–437. Marnett,L.J. (2003) Malondialdehyde, a product of lipid peroxida- 48. Pathak,M.A., Zarebska,Z., Mihm,M.C.,Jr, Jarzabek- tion, is mutagenic in human cells. J. Biol. Chem., 278, 31426–31433. Chorzelska,M., Chorzelski,T. and Jablonska,S. (1986) Detection of 67. Esterbauer,H. (1993) Cytotoxicity and genotoxicity of lipid- DNA-psoralen photoadducts in mammalian skin. J. Invest. oxidation products. Am. J. Clin. Nutr., 57, 779S–785S, discussion. Dermatol., 86, 308–315. 68. Harman,D. (1956) Aging: a theory based on free radical and 49. Wolff,K. (1990) Side-effects of psoralen photochemotherapy radiation chemistry. J. Gerontol., 11, 298–300. (PUVA). Br J Dermatol, 122(Suppl. 36), 117–125. 69. de Magalhaes,J.P. and Church,G.M. (2006) Cells discover fire: 50. Sator,P.G., Schmidt,J.B. and Honigsmann,H. (2002) Objective employing reactive oxygen species in development and consequences assessment of photoageing effects using high-frequency ultrasound for aging. Exp. Gerontol., 41, 1–10. in PUVA-treated psoriasis patients. Br. J. Dermatol., 147, 291–298. 70. Droge,W. and Schipper,H.M. (2007) Oxidative stress and aberrant 51. Wlaschek,M., Ma,W., Jansen-Durr,P. and Scharffetter- signaling in aging and cognitive decline. Aging Cell, 6, 361–370. Kochanek,K. (2003) Photoaging as a consequence of natural and 71. Percy,C., Pat,B., Poronnik,P. and Gobe,G. (2005) Role of oxidative therapeutic ultraviolet irradiation–studies on PUVA-induced senes- stress in age-associated chronic kidney pathologies. Adv. Chronic cence-like growth arrest of human dermal fibroblasts. Exp. Kidney Dis., 12, 78–83. Gerontol., 38, 1265–1270. 72. Csiszar,A., Toth,J., Peti-Peterdi,J. and Ungvari,Z. (2007) The aging 52. Herrmann,G., Brenneisen,P., Wlaschek,M., Wenk,J., Faisst,K., kidney: role of endothelial oxidative stress and inflammation. Acta Quel,G., Hommel,C., Goerz,G., Ruzicka,T. et al. (1998) Psoralen Physiol. Hung., 94, 107–115. photoactivation promotes morphological and functional changes in 73. Anantharaju,A., Feller,A. and Chedid,A. (2002) Aging liver. a fibroblasts in vitro reminiscent of cellular senescence. J. Cell. Sci., review. Gerontology, 48, 343–353. 111(Pt 6), 759–767. 74. Rohrbach,S., Niemann,B., Abushouk,A.M. and Holtz,J. (2006) 53. Ma,W., Hommel,C., Brenneisen,P., Peters,T., Smit,N., Sedivy,J., Caloric restriction and mitochondrial function in the ageing Scharffetter-Kochanek,K. and Wlaschek,M. (2003) Long-term myocardium. Exp. Gerontol., 41, 525–531. growth arrest of PUVA-treated fibroblasts in G2/M in the absence 75. Van Remmen,H. and Richardson,A. (2001) Oxidative damage to of p16(INK4a) p21(CIP1) or p53. Exp. Dermatol., 12, 629–637. mitochondria and aging. Exp. Gerontol., 36, 957–968. 54. Ma,W., Wlaschek,M., Hommel,C., Schneider,L.A. and Scharffetter- 76. Carrera-Rotllan,J. and Estrada-Garcia,L. (1998) Age-dependent Kochanek,K. (2002) Psoralen plus UVA (PUVA) induced pre- changes and interrelations of number of cells and biochemical mature senescence as a model for stress-induced premature parameters (glucose, triglycerides, TBARS, calcium, phosphorus) in senescence. Exp. Gerontol., 37, 1197–1201. cultured human vein endothelial cells. Mech. Ageing Dev., 55. Borlon,C., Debacq-Chainiaux,F., Hinrichs,C., Scharffetter- 103, 13–26. Kochanek,K., Toussaint,O. and Wlaschek,M. (2007) The gene 77. Ando,K., Beppu,M. and Kikugawa,K. (1995) Evidence for accu- expression profile of psoralen plus UVA-induced premature mulation of lipid hydroperoxides during the aging of human red senescence in skin fibroblasts resembles a combined DNA-damage blood cells in the circulation. Biol. Pharm. Bull., 18, 659–663. and stress-induced cellular senescence response phenotype. Exp. 78. Stolzing,A., Sethe,S. and Scutt,A.M. (2006) Stressed stem cells: Gerontol, 42, 911–923. temperature response in aged mesenchymal stem cells. Stem Cells 56. Hovest,M.G., Bruggenolte,N., Hosseini,K.S., Krieg,T. and Dev., 15, 478–487. Herrmann,G. (2006) Senescence of human fibroblasts after psoralen 79. Voss,P. and Siems,W. (2006) Clinical oxidation parameters of aging. photoactivation is mediated by ATR kinase and persistent DNA Free Radic. Res., 40, 1339–1349. damage foci at telomeres. Mol. Biol. Cell, 17, 1758–1767. 80. Droge,W. (2002) Free radicals in the physiological control of cell 57. Majka,J. and Burgers,P.M. (2007) Clamping the Mec1/ATR function. Physiol. Rev., 82, 47–95. checkpoint kinase into action. Cell Cycle, 6, 1157–1160. 81. Wei,Y.H. and Lee,H.C. (2002) Oxidative stress, mitochondrial 58. Cardone,J.M., Revers,L.F., Machado,R.M., Bonatto,D., DNA mutation, and impairment of antioxidant enzymes in aging. Brendel,M. and Henriques,J.A. (2006) Psoralen-sensitive mutant Exp. Biol. Med., 227, 671–682. 7574 Nucleic Acids Research, 2007, Vol. 35, No. 22 82. Arnould,S., Spanswick,V.J., Macpherson,J.S., Hartley,J.A., life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science, 292, 104–106. Thurston,D.E., Jodrell,D.I. and Guichard,S.M. (2006) Time- 100. Flurkey,K., Papaconstantinou,J., Miller,R.A. and Harrison,D.E. dependent cytotoxicity induced by SJG-136 (NSC 694501): (2001) Lifespan extension and delayed immune and collagen aging influence of the rate of interstrand cross-link formation on DNA in mutant mice with defects in growth hormone production. damage signaling. Mol. Cancer Ther., 5, 1602–1609. 83. O’Driscoll,M., Dobyns,W.B., van Hagen,J.M. and Jeggo,P.A. Proc. Natl Acad. Sci. USA, 98, 6736–6741. 101. Bluher,M., Kahn,B.B. and Kahn,C.R. (2003) Extended longevity (2007) Cellular and Clinical Impact of Haploinsufficiency in mice lacking the insulin receptor in adipose tissue. Science, for Genes Involved in ATR Signaling. Am. J. Hum. Genet., 299, 572–574. 81, 77–86. 102. Bartke,A. (2005) Minireview: role of the growth hormone/ 84. Niedernhofer,L.J., Odijk,H., Budzowska,M., van Drunen,E., insulin-like growth factor system in mammalian aging. Maas,A., Theil,A.F., de Wit,J., Jaspers,N.G., Beverloo,H.B. et al. Endocrinology, 146, 3718–3723. (2004) The structure-specific endonuclease Ercc1-Xpf is required to 103. Kirschner,K., Singh,R., Prost,S. and Melton,D.W. (2007) resolve DNA interstrand cross-link-induced double-strand breaks. Characterisation of Ercc1 deficiency in the liver and in conditional Mol. Cell. Biol., 24, 5776–5787. Ercc1-deficient primary hepatocytes in vitro. DNA Repair, 85. Clingen,P.H., Arlett,C.F., Hartley,J.A. and Parris,C.N. (2007) 6, 304–316. Chemosensitivity of primary human fibroblasts with defective 104. Prasher,J.M., Lalai,A.S., Heijmans-Antonissen,C., unhooking of DNA interstrand cross-links. Exp. Cell Res., Ploemacher,R.E., Hoeijmakers,J.H., Touw,I.P. and 313, 753–760. Niedernhofer,L.J. (2005) Reduced hematopoietic reserves in DNA 86. McWhir,J., Selfridge,J., Harrison,D.J., Squires,S. and –/– interstrand crosslink repair-deficient Ercc1 mice. EMBO J., Melton,D.W. (1993) Mice with DNA repair gene (ERCC-1) 24, 861–871. deficiency have elevated levels of p53, liver nuclear abnormalities 105. Pepper,C., Lowe,H., Fegan,C., Thurieau,C., Thurston,D.E., and die before weaning. Nat. Genet., 5, 217–224. Hartley,J.A. and Delavault,P. (2007) Fludarabine-mediated sup- 87. Weeda,G., Donker,I., de Wit,J., Morreau,H., Janssens,R., pression of the excision repair enzyme ERCC1 contributes to the Vissers,C.J., Nigg,A., van Steeg,H., Bootsma,D. et al. (1997) cytotoxic synergy with the DNA minor groove crosslinking agent Disruption of mouse ERCC1 results in a novel repair syndrome SJG-136 (NSC 694501) in chronic lymphocytic leukaemia cells. with growth failure, nuclear abnormalities and senescence. Curr. Br. J. Cancer, 97, 253–259. Biol., 7, 427–439. 106. Yang,L.Y., Li,L., Keating,M.J. and Plunkett,W. (1995) 88. Tian,M., Shinkura,R., Shinkura,N. and Alt,F.W. (2004) Growth Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and retardation, early death, and DNA repair defects in mice deficient inhibits cisplatin-DNA cross-link repair. Mol. Pharmacol., for the nucleotide excision repair enzyme XPF. Mol. Cell. Biol., 47, 1072–1079. 24, 1200–1205. 107. Moufarij,M.A., Sampath,D., Keating,M.J. and Plunkett,W. (2006) 89. Hasty,P., Campisi,J., Hoeijmakers,J., van Steeg,H. and Vijg,J. Fludarabine increases oxaliplatin cytotoxicity in normal and (2003) Aging and genome maintenance: lessons from the mouse? chronic lymphocytic leukemia lymphocytes by suppressing inter- Science, 299, 1355–1359. strand DNA crosslink removal. Blood, 108, 4187–4193. 90. Jaspers,N.G., Raams,A., Silengo,M.C., Wijgers,N., 108. Li,L., Keating,M.J., Plunkett,W. and Yang,L.Y. (1997) Niedernhofer,L.J., Robinson,A.R., Giglia-Mari,G., Fludarabine-mediated repair inhibition of cisplatin-induced DNA Hoogstraten,D., Kleijer,W.J. et al. (2007) First reported patient lesions in human chronic myelogenous leukemia-blast crisis K562 with human ERCC1 deficiency has cerebro-oculo-facio-skeletal cells: induction of synergistic cytotoxicity independent of reversal syndrome with a mild defect in nucleotide excision repair and of apoptosis resistance. Mol. Pharmacol., 52, 798–806. severe developmental failure. Am. J. Hum. Genet., 80, 457–466. 109. Montillo,M., Ricci,F. and Tedeschi,A. (2006) Role of fludarabine 91. Radford,S.J., Goley,E., Baxter,K., McMahan,S. and Sekelsky,J. in hematological malignancies. Expert Rev. Anticancer Ther., (2005) Drosophila ERCC1 is required for a subset of MEI-9- 6, 1141–1161. dependent meiotic crossovers. Genetics, 170, 1737–1745. 110. Tischkowitz,M. and Dokal,I. (2004) Fanconi anaemia and 92. Shannon,M., Lamerdin,J.E., Richardson,L., leukaemia - clinical and molecular aspects. Br. J. Haematol., McCutchen-Maloney,S.L., Hwang,M.H., Handel,M.A., Stubbs,L. 126, 176–191. and Thelen,M.P. (1999) Characterization of the mouse Xpf DNA 111. Ciccia,A., Ling,C., Coulthard,R., Yan,Z., Xue,Y., Meetei,A.R., repair gene and differential expression during spermatogenesis. Laghmani el,H., Joenje,H., McDonald,N. et al. (2007) Genomics, 62, 427–435. Identification of FAAP24, a Fanconi anemia core complex protein 93. Zhu,X.D., Niedernhofer,L., Kuster,B., Mann,M., that interacts with FANCM. Mol. Cell, 25, 331–343. Hoeijmakers,J.H. and de Lange,T. (2003) ERCC1/XPF removes 112. Niedernhofer,L.J. (2007) The Fanconi anemia signalosome anchor. the 3’ overhang from uncapped telomeres and represses formation Mol. Cell, 25, 487–490. of telomeric DNA-containing double minute chromosomes. Mol. 113. Taniguchi,T. and D’Andrea,A.D. (2006) Molecular patho- Cell, 12, 1489–1498. genesis of Fanconi anemia: recent progress. Blood, 94. Wu,Y., Zacal,N.J., Rainbow,A.J. and Zhu,X.D. (2007) XPF with 107, 4223–4233. mutations in its conserved nuclease domain is defective in DNA 114. Schroeder-Kurth,T. (2007) Fanconi anemia. a paradigmatic repair but functions in TRF2-mediated telomere shortening. DNA. disease for the understanding of cancer and aging. Repair, 6, 157–166. In Schindler,D.H.H. (ed.), Monographic Human Genetics, Vol. 15; 95. Zhang,N., Zhang,X., Peterson,C., Li,L. and Legerski,R. (2000) Karger, Basel, pp. 1–8. Differential processing of UV mimetic and interstrand crosslink 115. Ball,S.E., Gibson,F.M., Rizzo,S., Tooze,J.A., Marsh,J.C. and damage by XPF cell extracts. Nucleic Acids Res., 28, 4800–4804. Gordon-Smith,E.C. (1998) Progressive telomere shortening in 96. Niedernhofer,L.J., Garinis,G.A., Raams,A., Lalai,A.S., aplastic anemia. Blood, 91, 3582–3592. Robinson,A.R., Appeldoorn,E., Odijk,H., Oostendorp,R., 116. Leteurtre,F., Li,X., Guardiola,P., Le Roux,G., Sergere,J.C., Ahmad,A. et al. (2006) A new progeroid syndrome reveals that Richard,P., Carosella,E.D. and Gluckman,E. (1999) Accelerated genotoxic stress suppresses the somatotroph axis. Nature, telomere shortening and telomerase activation in Fanconi’s 444, 1038–1043. anaemia. Br. J. Haematol., 105, 883–893. 97. Fabrizio,P., Pozza,F., Pletcher,S.D., Gendron,C.M. and 117. Hanson,H., Mathew,C.G., Docherty,Z. and Mackie Ogilvie,C. Longo,V.D. (2001) Regulation of longevity and stress resistance (2001) Telomere shortening in Fanconi anaemia by Sch9 in yeast. Science, 292, 288–290. demonstrated by a direct FISH approach. Cytogenet. Cell Genet., 98. Kenyon,C., Chang,J., Gensch,E., Rudner,A. and Tabtiang,R. 93, 203–206. (1993) A C. elegans mutant that lives twice as long as wild type. 118. Cabuy,E., Newton,C., Joksic,G., Woodbine,L., Koller,B., Nature, 366, 461–464. Jeggo,P.A. and Slijepcevic,P. (2005) Accelerated telomere short- 99. Clancy,D.J., Gems,D., Harshman,L.G., Oldham,S., Stocker,H., ening and telomere abnormalities in radiosensitive cell lines. Hafen,E., Leevers,S.J. and Partridge,L. (2001) Extension of Radiat. Res., 164, 53–62. Nucleic Acids Research, 2007, Vol. 35, No. 22 7575 119. Thompson,K.V. and Holliday,R. (1983) Genetic effects on the 139. Otterlei,M., Bruheim,P., Ahn,B., Bussen,W., Karmakar,P., longevity of cultured human fibroblasts. II. DNA repair deficient Baynton,K. and Bohr,V.A. (2006) Werner syndrome protein syndromes. Gerontology, 29, 83–88. participates in a complex with RAD51, RAD54, RAD54B and 120. Adelfalk,C., Lorenz,M., Serra,V., von Zglinicki,T., Hirsch- ATR in response to ICL-induced replication arrest. J. Cell. Sci., Kauffmann,M. and Schweiger,M. (2001) Accelerated telomere 119, 5137–5146. shortening in Fanconi anemia fibroblasts–a longitudinal study. 140. Dhillon,K.K., Sidorova,J., Saintigny,Y., Poot,M., Gollahon,K., FEBS Lett., 506, 22–26. Rabinovitch,P.S. and Monnat,R.J.Jr. (2007) Functional role of 121. Callen,E., Samper,E., Ramirez,M.J., Creus,A., Marcos,R., the Werner syndrome RecQ helicase in human fibroblasts. Ortega,J.J., Olive,T., Badell,I., Blasco,M.A. et al. (2002) Breaks at Aging Cell, 6, 53–61. telomeres and TRF2-independent end fusions in Fanconi anemia. 141. Saffi,J., Feldmann,H., Winnacker,E.L. and Henriques,J.A. (2001) Hum. Mol. Genet., 11, 439–444. Interaction of the yeast Pso5/Rad16 and Sgs1 proteins: influences 122. Bagby,G.C.,Jr (2003) Genetic basis of Fanconi anemia. Curr. on DNA repair and aging. Mutat. Res., 486, 195–206. Opin. Hematol., 10, 68–76. 142. Brendel,M., Bonatto,D., Strauss,M., Revers,L.F., Pungartnik,C., 123. Bogliolo,M., Cabre,O., Callen,E., Castillo,V., Creus,A., Marcos,R. Saffi,J. and Henriques,J.A. (2003) Role of PSO genes in repair of and Surralles,J. (2002) The Fanconi anaemia genome stability and DNA damage of Saccharomyces cerevisiae. Mutat. Res., tumour suppressor network. Mutagenesis, 17, 529–538. 544, 179–193. 124. Li,X., Leteurtre,F., Rocha,V., Guardiola,P., Berger,R., 143. von Kobbe,C., Karmakar,P., Dawut,L., Opresko,P., Zeng,X., Daniel,M.T., Noguera,M.H., Maarek,O., Roux,G.L. et al. (2003) Brosh,R.M.,Jr, Hickson,I.D. and Bohr,V.A. (2002) Colocalization, Abnormal telomere metabolism in Fanconi’s anaemia correlates physical, and functional interaction between Werner and Bloom with genomic instability and the probability of developing severe syndrome proteins. J. Biol. Chem., 277, 22035–22044. aplastic anaemia. Br. J. Haematol., 120, 836–845. 144. Pichierri,P., Franchitto,A. and Rosselli,F. (2004) BLM and the 125. Donoho,G., Brenneman,M.A., Cui,T.X., Donoviel,D., Vogel,H., FANC proteins collaborate in a common pathway in response to Goodwin,E.H., Chen,D.J. and Hasty,P. (2003) Deletion of Brca2 stalled replication forks. EMBO J., 23, 3154–3163. exon 27 causes hypersensitivity to DNA crosslinks, chromosomal 145. Slupianek,A., Gurdek,E., Koptyra,M., Nowicki,M.O., instability, and reduced life span in mice. Genes Chromosomes Siddiqui,K.M., Groden,J. and Skorski,T. (2005) BLM helicase is Cancer, 36, 317–331. activated in BCR/ABL leukemia cells to modulate responses to 126. Zhang,X., Li,J., Sejas,D.P. and Pang,Q. (2005) Hypoxia- cisplatin. Oncogene, 24, 3914–3922. reoxygenation induces premature senescence in FA bone marrow 146. Cheng,W.H., von Kobbe,C., Opresko,P.L., Arthur,L.M., hematopoietic cells. Blood, 106, 75–85. Komatsu,K., Seidman,M.M., Carney,J.P. and Bohr,V.A. (2004) 127. Zhang,X., Sejas,D.P., Qiu,Y., Williams,D.A. and Pang,Q. (2007) Linkage between Werner syndrome protein and the Mre11 Inflammatory ROS promote and cooperate with the Fanconi complex via Nbs1. J. Biol. Chem., 279, 21169–21176. anemia mutation for hematopoietic senescence. J. Cell. Sci., 147. Hirano,S., Yamamoto,K., Ishiai,M., Yamazoe,M., Seki,M., 120, 1572–1583. Matsushita,N., Ohzeki,M., Yamashita,Y.M., Arakawa,H. et al. 128. Duckworth-Rysiecki,G. and Taylor,A.M. (1985) Effects of (2005) Functional relationships of FANCC to homologous ionizing radiation on cells from Fanconi’s anemia patients. recombination, translesion synthesis, and BLM. EMBO J., Cancer Res., 45, 416–420. 24, 418–427. 129. Carreau,M., Alon,N., Bosnoyan-Collins,L., Joenje,H. and 148. Franchitto,A. and Pichierri,P. (2002) Bloom’s syndrome protein is Buchwald,M. (1999) Drug sensitivity spectra in Fanconi anemia required for correct relocalization of RAD50/MRE11/NBS1 lymphoblastoid cell lines of defined complementation groups. complex after replication fork arrest. J. Cell. Biol., 157, 19–30. Mutat. Res., 435, 103–109. 149. Zhang,R., Sengupta,S., Yang,Q., Linke,S.P., Yanaihara,N., 130. Tebbs,R.S., Hinz,J.M., Yamada,N.A., Wilson,J.B., Salazar,E.P., Bradsher,J., Blais,V., McGowan,C.H. and Harris,C.C. (2005) Thomas,C.B., Jones,I.M., Jones,N.J. and Thompson,L.H. (2005) BLM helicase facilitates Mus81 endonuclease activity in human New insights into the Fanconi anemia pathway from an isogenic cells. Cancer Res., 65, 2526–2531. FancG hamster CHO mutant. DNA Repair, 4, 11–22. 150. Hanada,K., Budzowska,M., Modesti,M., Maas,A., Wyman,C., 131. Taniguchi,T., Garcia-Higuera,I., Xu,B., Andreassen,P.R., Essers,J. and Kanaar,R. (2006) The structure-specific endonuclease Gregory,R.C., Kim,S.T., Lane,W.S., Kastan,M.B. and Mus81-Eme1 promotes conversion of interstrand DNA crosslinks D’Andrea,A.D. (2002) Convergence of the fanconi anemia and into double-strands breaks. EMBO J., 25, 4921–4932. ataxia telangiectasia signaling pathways. Cell, 109, 459–472. 151. Trowbridge,K., McKim,K., Brill,S.J. and Sekelsky,J. (2007) 132. Zhang,N., Liu,X., Li,L. and Legerski,R. (2007) Double-strand Synthetic lethality in the absence of the Drosophila MUS81 breaks induce homologous recombinational repair of interstrand endonuclease and the DmBlm helicase is associated with elevated cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and apoptosis. Genetics, 176, 1993–2001. the Fanconi anemia pathway. DNA Repair, 6, 1670–1678. 152. Martin,G.M. and Oshima,J. (2000) Lessons from human proger- 133. Hinz,J.M., Nham,P.B., Salazar,E.P. and Thompson,L.H. (2006) oid syndromes. Nature, 408, 263–266. The Fanconi anemia pathway limits the severity of mutagenesis. 153. Crabbe,L., Jauch,A., Naeger,C.M., Holtgreve-Grez,H. and DNA Repair, 5, 875–884. Karlseder,J. (2007) Telomere dysfunction as a cause of genomic 134. Lee,J.W., Harrigan,J., Opresko,P.L. and Bohr,V.A. (2005) instability in Werner syndrome. Proc. Natl Acad. Sci. USA, Pathways and functions of the Werner syndrome protein. Mech. 104, 2205–2210. Ageing Dev., 126, 79–86. 154. Goldstein,S. and Harley,C.B. (1979) In vitro studies of age- 135. Poot,M., Gollahon,K.A., Emond,M.J., Silber,J.R. and associated diseases. Fed. Proc., 38, 1862–1867. Rabinovitch,P.S. (2002) Werner syndrome diploid fibroblasts are 155. Du,X., Shen,J., Kugan,N., Furth,E.E., Lombard,D.B., Cheung,C., sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen: Pak,S., Luo,G., Pignolo,R.J. et al. (2004) Telomere shortening implications for the disease phenotype. FASEB J., 16, 757–758. exposes functions for the mouse Werner and Bloom syndrome 136. Poot,M., Yom,J.S., Whang,S.H., Kato,J.T., Gollahon,K.A. and genes. Mol. Cell. Biol., 24, 8437–8446. Rabinovitch,P.S. (2001) Werner syndrome cells are sensitive to 156. Sarkar,S., Davies,A.A., Ulrich,H.D. and McHugh,P.J. (2006) DNA cross-linking drugs. FASEB J., 15, 1224–1226. DNA interstrand crosslink repair during G1 involves nucleotide 137. Cheng,W.H., Kusumoto,R., Opresko,P.L., Sui,X., Huang,S., excision repair and DNA polymerase zeta. EMBO J., Nicolette,M.L., Paull,T.T., Campisi,J., Seidman,M. et al. (2006) 25, 1285–1294. Collaboration of Werner syndrome protein and BRCA1 in cellular 157. Bonatto,D., Revers,L.F., Brendel,M. and Henriques,J.A. (2005) responses to DNA interstrand cross-links. Nucleic Acids Res., The eukaryotic Pso2/Snm1/Artemis proteins and their function as 34, 2751–2760. genomic and cellular caretakers. Braz. J. Med. Biol. Res., 138. Zhang,N., Kaur,R., Lu,X., Shen,X., Li,L. and Legerski,R.J. 38, 321–334. (2005) The Pso4 mRNA splicing and DNA repair complex 158. Dronkert,M.L., de Wit,J., Boeve,M., Vasconcelos,M.L., van interacts with WRN for processing of DNA interstrand cross- Steeg,H., Tan,T.L., Hoeijmakers,J.H. and Kanaar,R. (2000) links. J. Biol. Chem., 280, 40559–40567. Disruption of mouse SNM1 causes increased sensitivity to the 7576 Nucleic Acids Research, 2007, Vol. 35, No. 22 DNA interstrand cross-linking agent mitomycin C. Mol. Cell. can restore the defect in mutagenesis of the pso4-1 mutant of Biol., 20, 4553–4561. S. cerevisiae. Mutat. Res., 314, 209–220. 159. Demuth,I., Digweed,M. and Concannon,P. (2004) Human 170. Morais Junior,M.A., Vicente,E.J., Brozmanova,J., Schenberg,A.C. SNM1B is required for normal cellular response to both DNA and Henriques,J.A. (1996) Further characterization of the yeast interstrand crosslink-inducing agents and ionizing radiation. pso4-1 mutant: interaction with rad51 and rad52 mutants after Oncogene, 23, 8611–8618. photoinduced psoralen lesions. Curr. Genet., 29, 211–218. 160. Ahkter,S., Richie,C.T., Zhang,N., Behringer,R.R., Zhu,C. and 171. Grillari,J., Hohenwarter,O., Grabherr,R.M. and Katinger,H. Legerski,R.J. (2005) Snm1-deficient mice exhibit accelerated (2000) Subtractive hybridization of mRNA from early passage and tumorigenesis and susceptibility to infection. Mol. Cell. Biol., senescent endothelial cells. Exp. Gerontol., 35, 187–197. 25, 10071–10078. 172. Voglauer,R., Chang,M.W., Dampier,B., Wieser,M., Baumann,K., 161. van Overbeek,M. and de Lange,T. (2006) Apollo, an Artemis- Sterovsky,T., Schreiber,M., Katinger,H. and Grillari,J. (2006) related nuclease, interacts with TRF2 and protects human SNEV overexpression extends the life span of human endothelial telomeres in S phase. Curr. Biol., 16, 1295–1302. cells. Exp. Cell Res., 312, 746–759. 162. Freibaum,B.D. and Counter,C.M. (2006) hSnm1B is a novel 173. Fortschegger,K., Wagner,B., Voglauer,R., Katinger,H., Sibilia,M. telomere-associated protein. J. Biol. Chem., 281, 15033–15036. and Grillari,J. (2007) Early embryonic lethality of mice lacking the 163. Lenain,C., Bauwens,S., Amiard,S., Brunori,M., Giraud-Panis,M.J. essential protein SNEV. Mol. Cell. Biol., 27, 3123–3130. and Gilson,E. (2006) The Apollo 5’ exonuclease functions together 174. Schraml,E., Voglauer,R., Fortschegger,K., Sibilia,M., Grillari,J. with TRF2 to protect telomeres from DNA repair. Curr. Biol., and Schauenstein,K. (in press) The expression of mSNEV, the 16, 1303–1310. murine homologue of human senescence evasion factor 164. Mahajan,K.N. and Mitchell,B.S. (2003) Role of human Pso4 in (SNEVPrp19/Pso4), is associated with the self-renewal capacity of mammalian DNA repair and association with terminal deoxynu- hematopoietic stem cells. Stem Cells Dev. cleotidyl transferase. Proc. Natl Acad. Sci. USA, 100, 10746–10751. 175. Ajuh,P., Kuster,B., Panov,K., Zomerdijk,J.C., Mann,M. and 165. Lu,X. and Legerski,R.J. (2007) The Prp19/Pso4 core complex Lamond,A.I. (2000) Functional analysis of the human CDC5L undergoes ubiquitylation and structural alterations in response to complex and identification of its components by mass spectro- DNA damage. Biochem. Biophys. Res. Commun., 354, 968–974. metry. EMBO J., 19, 6569–6581. 166. Grey,M., Dusterhoft,A., Henriques,J.A. and Brendel,M. (1996) 176. Hatakeyama,S., Yada,M., Matsumoto,M., Ishida,N. and Allelism of PSO4 and PRP19 links pre-mRNA processing with Nakayama,K.I. (2001) U-Box proteins as a new family of recombination and error-prone DNA repair in Saccharomyces ubiquitin-protein ligases. J. Biol. Chem., 276, 33111–33120. cerevisiae. Nucleic Acids Res., 24, 4009–4014. 177. Loscher,M., Fortschegger,K., Ritter,G., Wostry,M., 167. Grillari,J., Ajuh,P., Stadler,G., Loscher,M., Voglauer,R., Voglauer,R., Schmid,J.A., Watters,S., Rivett,A.J., Ajuh,P. et al. Ernst,W., Chusainow,J., Eisenhaber,F., Pokar,M. et al. (2005) (2005) Interaction of U-box E3 ligase SNEV with PSMB4, SNEV is an evolutionarily conserved splicing factor whose the beta7 subunit of the 20 S proteasome. Biochem. J., oligomerization is necessary for spliceosome assembly. Nucleic 388, 593–603. Acids Res., 33, 6868–6883. 178. Cho,S.Y., Shin,E.S., Park,P.J., Shin,D.W., Chang,H.K., Kim,D., 168. Henriques,J.A., Vicente,E.J., Leandro da Silva,K.V. and Lee,H.H., Lee,J.H., Kim,S.H. et al. (2006) Identification of mouse Schenberg,A.C. (1989) PSO4: a novel gene involved in error- Prp19p as a lipid droplet-associated protein and its possible prone repair in Saccharomyces cerevisiae. Mutat. Res., involvement in the biogenesis of lipid droplets. J. Biol. Chem., 218, 111–124. 20, 20. 169. Morais Junior,M.A., Brozmanova,J., Benfato,M.S., Duraj,J., 179. Kirkwood,T.B. (2005) Understanding the odd science of aging. Vlckova,V. and Henriques,J.A. (1994) The E. coli recA gene Cell, 120, 437–447.

Journal

Nucleic Acids ResearchOxford University Press

Published: Dec 14, 2007

There are no references for this article.