Unpaved roads: How the DNA damage response navigates endogenous genotoxins

Accurate DNA repair is essential for cellular and organismal homeostasis, and DNA repair defects result in genetic diseases and cancer predisposition. Several environmental factors, such as ultraviolet light, damage DNA, but many other molecules with DNA damaging potential are byproducts of normal cellular processes. In this review, we highlight some of the prominent sources of endogenous DNA damage as well as their mechanisms of repair, with a special focus on repair by the homologous recombination and Fanconi anemia pathways. We also discuss how modulating DNA damage caused by endogenous factors may augment current approaches used to treat BRCA-deficient cancers. Finally, we describe how synthetic lethal interactions may be exploited to exacerbate DNA repair deficiencies and cause selective toxicity in additional types of cancers.