First, the free DNA ends are recognized by DSB sensors, followed by 5′-3′ resection of the DNA ends. HR has multiple steps and requires extensive processing of DNA ends ( Symington 2014). For recent reviews of NHEJ, which is not covered in detail here, please refer to, for example, Thompson (2012) and Chiruvella et al. Derivatives of NHEJ such as microhomology-mediated end joining (MMEJ) or alternative NHEJ (alt-NHEJ) require more substantial processing and may lead to the loss of genetic information. NHEJ is basically a ligation reaction of two DNA ends that are only minimally processed. 2013), with NHEJ being the predominant pathway in mammals outside of S phase. Indeed, the choice of pathways is to a significant extent not stochastic but a function of the cell cycle ( Ferretti et al. Although HR requires a template such as a sister chromatid or a homologous chromosome and is limited to S and G 2 phases of the cell cycle, NHEJ is template-independent and can occur in all cell cycle states. 2001a, b Hanahan and Weinberg 2011).īeside HR, DSBs can also be repaired by nonhomologous end joining (NHEJ). Failure to repair DSBs can lead to cell death or gross chromosomal aberrations, which in humans are a hallmark of cancer ( Myung et al.

In special cellular states, programmed DSBs are introduced by endonucleases to initiate the generation of genetic variability by processes such as meiotic recombination of homologous chromosomes ( Lam and Keeney 2014 Zickler and Kleckner 2014), V(D)J and class switch recombination to generate antibody diversity and yeast-mating-type switching ( Gapud and Sleckman 2011 Haber 2012 Xu et al. 2000 Aguilera and Gomez-Gonzalez 2008 Cadet et al. HR is initiated by single unprotected DNA ends, which arise at collapsed replication forks and unprotected telomeres, or by DNA double-strand breaks (DSBs), which are products of ionizing radiation, reactive oxygen species, genotoxic chemicals, or abortive topoisomerase reactions ( Sutherland et al.

All domains of life maintain genomes and ensure genetic diversity through homologous recombination (HR) or homology directed repair.

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