Changing modes of double-strand break repair

A large body of very recent work has revealed an intimate connection between DNA repair and aging. Specifically, the work of several labs has shown that mutants deficient in the type of DNA repair known as nucleotide excision repair (NER) display dramatically accelerated aging phenotypes, despite their fervent attempts to direct energy away from growth and toward cellular maintenance (see our earlier articles How premature aging resembles calorie restriction and More on DNA damange and the somatotroph axis).

A recent review by Engels et al. discusses the relationship between repair of another type of damage — double-strand breaks (DSBs) — and the phenotypes of aging, and discusses emerging evidence that the mode of DSB repair shifts during aging from non-homologous end-joining to the use of homologous information on sister chromatids to fix damage.

Until recently, the connection between aging and DNA repair has rested on two classes of observation. First, DNA damage and unrepaired double-strand breaks (DSBs) accumulate with age. Second, several defects in DNA repair genes are associated with early onset of age-related diseases and other signs of premature aging. Now, a third link has emerged: The mechanisms by which cells repair DSB damage can change dramatically with age, shifting from simpler end-joining processes in younger organisms to homologous mechanisms in which missing genetic information is restored through use of a template. So far this third link between aging and DNA repair has only been observed in a small number of experimental systems, and cannot yet claim the generality of the other two. Here we review the evidence for this phenomenon and present new data testing models for the underlying causes. If the generality of age-related changes in DSB repair pathway usage can be established, it will provide a new insight into the underlying molecular basis of aging and how evolution has shaped these processes.

The two modes of DSB repair result in quite different mutational spectra, and could therefore have distinct impacts on the robustness of gene expression (q.v., Genomic instability and transcriptional noise).

As the authors themselves point out, it remains to be seen whether the phenomenon is widespread or limited to the systems in which the founding observations were made. Research aimed at determining its generality would have broad application: Given that DSBs are not only caused by endogenous cellular processes (such as oxidation), but also by cancer treatments such as radiation and chemotherapeutic agents, changes in DSB repair over the course of aging are of interest to biogerontologists and clinicians alike.