Fig. 1.

Summary of known double-stranded break (DSB) repair pathways. After initiation of a DSB, the initial repair pathway decision is between the binding of the dsDNA ends with Ku70/80 and subsequent error-prone NHEJ (bottom) or DNA end resection by the MRN complex, which is activated by CtIP (middle). Before extensive DNA end resection occurs, the micro-homologies between the exposed ssDNA ends can facilitate a second alternative error-prone repair mechanism, MMEJ. Alternatively, more extensive DNA end resection is carried out by EXO1 and DNA2, after which the exposed ssDNA is bound by RPA. This initiates one of two faithful repair mechanisms (top). When Rad51 is successfully loaded onto the ssDNA strand and a nucleofilament is therefore formed, the DSB can be resolved via HDR in the presence of a dsDNA donor. Alternatively, two other DSB resolution fates can occur: homologies within the exposed ssDNA may facilitate the third error-prone repair mechanism, SSA, or Rad52 may be loaded onto the ssDNA and can trigger the faithful repair mechanism, SSTR, if a ssODN template is present at the site of the DSB. Importantly, NHEJ, the main competitor of faithful repair mechanisms, can readily occur at the earliest stage in the DSB resolution process, with subsequent error-prone repair mechanisms still occurring either part way through and/or after extensive DNA end resection. By contrast, both known faithful repair mechanisms require extensive DNA end resection and can be subdivided into Rad51-dependent HDR and Rad51-independent SSTR. dsDNA, double-stranded DNA; HDR, homology-directed repair; indel, insertion or deletion; MMEJ, microhomology-mediated end joining; MRN, MRE11, Rad50 and NSB1; NHEJ, non-homologous end joining; SSA, single-strand annealing; ssODN, single-stranded oligodeoxynucleotide; SSTR, single-stranded template repair.