Ubiquitous overexpression of the DNA repair factor dPrp19
reduces DNA damage and extends Drosophila life span
, Hanna Dellago
, Martina Gáliková
, Markus Schosserer
, Thomas Flatt
and Johannes Grillari
Mechanisms that ensure and maintain the stability of genetic information are fundamentally important for organismal function and
can have a large impact on disease, aging, and life span. While a multi-layered cellular apparatus exists to detect and respond to
DNA damage, various insults from environmental and endogenous sources continuously affect DNA integrity. Over time this can
lead to the accumulation of somatic mutations, which is thought to be one of the major causes of aging. We have previously found
that overexpression of the essential human DNA repair and splicing factor SNEV, also called PRP19 or hPso4, extends replicative life
span of cultured human endothelial cells and impedes accumulation of DNA damage. Here, we show that adult-speciﬁc
overexpression of dPrp19, the D. melanogaster ortholog of human SNEV/PRP19/hPso4, robustly extends life span in female fruit ﬂies.
This increase in life span is accompanied by reduced levels of DNA damage and improved resistance to oxidative and genotoxic
stress. Our ﬁndings suggest that dPrp19 plays an evolutionarily conserved role in aging, life span modulation and stress resistance,
and support the notion that superior DNA maintenance is key to longevity.
npj Aging and Mechanisms of Disease (2017) 3:5 ; doi:10.1038/s41514-017-0005-z
Aging is characterized by a time-progressive decline of physiolo-
gical function at the level of cells, tissues, organs, and ultimately
affects the whole organism. According to the “disposable soma”
hypothesis of aging, this functional decline results from the
accumulation of stochastic damage, for example, due to somatic
mutations, and is counteracted by investment into somatic
maintenance and repair.
Accumulation of DNA damage due to
decreased repair can accelerate aging, as is observed in segmental
progeroid syndromes including the Werner or Hutchinson-Gilford
syndromes in humans
and mouse models.
exposure to DNA damaging agents, for instance during che-
motherapy, can lead to a phenotype of acquired premature
Accelerated accumulation of DNA damage
and premature aging phenotypes are typically well correlated, but
whether improved DNA damage repair (DDR) can extend
organismal life span remains largely unclear.
In the fruit ﬂy(Drosophila melanogaster), a well-studied model
for dissecting the mechanisms of aging, spontaneous somatic
mutations accumulate with age, and defective DNA repair is
associated with reduced life span.
However, overexpression of
DNA repair factors in the ﬂy seems to have highly variable,
sometimes contradictory effects that depend on sex, develop-
mental stage, and the tissue of intervention. For instance, poly
(ADP-ribose) polymerase-1 (PARP-1) modiﬁes histones, transcrip-
tion factors and repair enzymes in response to DNA breaks, and its
endogenous activity is well correlated with life span in several
In Drosophila, overexpression of PARP-1
prolongs life span in both sexes, yet only when restricted to the
adult nervous system.
Similarly, overexpression of Gadd45
(growth arrest and DNA damage 45) (ref. 9), a regulator of DNA
repair and cellular stress responses, in the nervous system
increases ﬂy life span but ubiquitous expression is lethal.
Indeed, a recent study by Shaposhnikov et al.
has found that
DNA repair factors can affect Drosophila life span and stress
resistance either positively or negatively, depending on the sex
and on whether overexpression is ubiquitous or limited to the
nervous system. Interestingly, all repair factors that were expressed
throughout the adult ﬂy body were found to shorten life span. In
another study, Barclay and colleagues examined the effects of
overexpression of several known D. melanogaster homologs of
human DNA repair genes on Drosophila life span in a genetic model
of spinocerebral ataxia (SCA), aiming to identify repair pathways
that might be relevant for SCA pathology. They found that an
extension of life span and improvement of SCA symptoms could
not be attributed to a single repair pathway; instead, each pathway
included factors that had either detrimental, beneﬁcial, or no effects
on life span.
Yet, these results—obtained in a diseased mutant
background—do not necessarily reﬂect possible life span effects of
DNA repair factors in healthy wild-type ﬂies. Thus, to date, the
relationship between DNA damage, repair and organismal aging
still remains poorly understood.
Here, we examine the role of adult-speciﬁc overexpression of
the DNA repair factor Prp19 (pre-messenger RNA (mRNA)
processing factor 19) in affecting life span, stress resistance, and
DNA damage in Drosophila. PRP19 (also called senescence evasion
factor, SNEV, or hPso4) was ﬁrst characterized in a yeast mutant
exhibiting increased sensitivity to DNA interstrand crosslinking
induced by treatment with psoralen and ultraviolet (UV)
Biochemically, PRP19 acts as an E3 ubiquitin ligase
and interacts with multiple players in the DNA repair pathways,
including each of the two core kinases, ATM (ataxia telangiectasia
mutated) and ATR (ataxia telangiectasia related).
Received: 26 September 2016 Revised: 15 February 2017 Accepted: 15 February 2017
Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland;
Department of Biotechnology, BOKU – University of Natural Resources and Life Sciences,
Vienna, Vienna, Austria;
Institut für Populationsgenetik, Vetmeduni Vienna, Vienna, Austria;
Department of Developmental Molecular Biology, Max Planck Institute for
Biophysical Chemistry, Göttingen, Germany;
Christian Doppler Laboratory on Biotechnology of Skin Aging, Dept. of Biotechnology, BOKU – University of Natural Resources and
Life Sciences, Vienna, Vienna, Austria and
Evercyte GmbH, Vienna, Austria
Correspondence: Markus Schosserer (email@example.com) and Thomas Flatt (thomas.ﬂatt@unil.ch)
Published in partnership with the Japanese Society of Anti-Aging Medicine