DNA double-strand breaks: a potential causative factor for mammalian aging?

Abstract

Aging is a pleiotropic and stochastic process influenced by both genetics and environment. As a result the fundamental underlying causes of aging are controversial and likely diverse. Genome maintenance and in particular the repair of DNA damage is critical to ensure longevity needed for reproduction and as a consequence imperfections or defects in maintaining the genome may contribute to aging. There are many forms of DNA damage with double-strand breaks (DSBs) being the most toxic. Here we discuss DNA DSBs as a potential causative factor for aging including factors that generate DNA DSBs, pathways that repair DNA DSBs, consequences of faulty or failed DSB repair and how these consequences may lead to age-dependent decline in fitness. At the end we compare mouse models of premature aging that are defective for repairing either DSBs or UV light-induced lesions. Based on these comparisons we believe the basic mechanisms responsible for their aging phenotypes are fundamentally different demonstrating the complex and pleiotropic nature of this process.

Fig. 1

Homologous recombination and gene conversion. (a) Homologous templates are aligned. This usually occurs between sister chromatids during DNA replication, but may also occur between chromosomes as shown here. The red chromosome has a DSB and a sequence difference (*) located close to the break. (b) The ends are resected to form single-strands. Note the sequence difference from the bottom red strand is removed. (c) The red single-strands invade the blue homologous template to form a joint molecule and primers for DNA replication (green arrows). Note the blue strands are used as templates for DNA replication; therefore, the green strands contain the same information as the blue strands. This means sequence differences on the resected red strand are lost (gene conversion). (d) The formation of Holliday junctions (a mobile attachment between four strands of DNA) and heteroduplexes (double-strand DNA composed of a strand from each homologue). Note the sequence difference is lost for one strand and a mismatch is formed for the other strand. (e) Noncrossover resolution of the Holliday junctions. Horizontal black lines represent locations where strands are cut. (f) The final products. For this diagram the top chromosome contains a mismatched that may be resolved by MMR. (g) Crossover resolution. The left Holliday junction is resolved as shown for the noncrossover event; however, the outer strands are cut to resolve the right Holliday junction. (g) The final products showing the chromosomes recombine. The heteroduplex and mismatch are the same as described for the noncrossover.

Fig. 2

DSBs as a causative factor in aging. DSBs are generated by a variety of sources including exposure to genotoxins and telomere erosion. Telomerase suppresses telomere erosion while HR and NHEJ repair DNA DSBs. Unrepaired DSBs induce anti-cancer responses that may induce apoptosis or cellular senescence. As an indirect consequence these responses may contribute to aging. DSBs may be incorrectly repaired to generate gross chromosomal rearrangements (GCRs). These rearrangements may lead to cancer but may also contribute to aging by inducing mitotic checkpoints or increasing transcriptional variation.