Double-strand DNA breaks (DSBs) are generated by ionizing radiation and as intermediates during the processing of DNA, such as repair of interstrand cross-links and collapsed replication forks. These potentially deleterious DSBs are repaired primarily by the homologous recombination (HR) and nonhomologous end joining (NHEJ) DNA repair pathways. HR utilizes a homologous template to accurately restore damaged DNA, whereas NHEJ utilizes microhomology to join breaks in close proximity. The pathway available for DSB repair is dependent upon the cell cycle stage; for example, HR primarily functions during the S/G2 stages while NHEJ can repair DSBs at any cell cycle stage. Posttranslational modifications (PTMs) promote activity of specific pathways and subpathways through enzyme activation and precisely timed protein recruitment and degradation. This chapter provides an overview of PTMs occurring during DSB repair. In addition, clinical phenotypes associated with HR-defective cancers, such as mutational signatures used to predict response to poly(ADP-ribose) polymerase inhibitors, are discussed. Understanding these processes will provide insight into mechanisms of genome maintenance and likely identify targets and new avenues for therapeutic interventions.
Keywords: Alternate end joining; Break induced replication; Chromosome integrity; Double-strand break repair; Homologous recombination; Nonhomologous end joining; PARP inhibitors; RAD51; Synthesis-dependent strand annealing; Ubiquitination.