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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. 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Nucleic Acids Research – Oxford University Press
Published: Dec 14, 2007
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