This review gives an account of how the cell repairs DNA damage and presents evidence that DNA damage contributes to aging and cancer, with the outcome dependent on the type and number of lesions in DNA. Examples of accelerated aging syndromes associated with defects in DNA repair mechanisms are contrasted with cancers.

A restricted diet extends the lives and improves the health of mice with accelerated ageing due to an inability to repair DNA damage. Dietary restriction is well established as an intervention that can extend lifespan and delay many signs of ageing in numerous species, but the underlying mechanisms remain unresolved. Jan Hoeijmakers and colleagues have examined the effects of dietary restriction in two mouse models with defective DNA repair that develop signs resembling those seen in human progeroid syndromes, which cause children to age at an accelerated rate. Strikingly, a dietary restriction of 30% substantially increased lifespan in both models and mice on the restricted diets maintained more neurons and better motor function than controls. In particular, the authors suggest DNA-repair-deficient Ercc1Δ/− mice as an effective model for the study of the effects of dietary restriction and for testing therapeutic interventions. Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/−) show numerous accelerated ageing features that limit their lifespan to 4-6 months1,2,3,4. They also exhibit a ‘survival response’, which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction)1,5. Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg−/− (also known as Ercc5−/−) mice, a model of Cockayne syndrome6, responded similarly. The dietary restriction response in Ercc1∆/− mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/− mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/− mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

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Primary DNA damage sensing in mammalian global genome nucleotide excision repair (GG-NER) is performed by the xeroderma pigmentosum group C (XPC)/HR23B protein complex. HR23B and HR23A are human homologs of the yeast ubiquitin-domain repair factor RAD23, the function of which is unknown. Knockout mice revealed thatmHR23AandmHR23Bhave a fully redundant role in NER, and a partially redundant function in embryonic development. Inactivation of both genes causes embryonic lethality, but appeared still compatible with cellular viability. Analysis ofmHR23A/Bdouble-mutant cells showed that HR23 proteins function in NER by governing XPC stability via partial protection against proteasomal degradation. Interestingly, NER-type DNA damage further stabilizes XPC and thereby enhances repair. These findings resolve the primary function of RAD23 in repair and reveal a novel DNA-damage-dependent regulation mechanism of DNA repair in eukaryotes, which may be part of a more global damage-response circuitry.