Fig. 1.

DSB repair pathways. Choice of the pathway is initially determined by 53BP1 and BRCA1, with 53BP1 promoting NHEJ and BRCA1 stimulating HR. NHEJ begins with Ku70‐Ku80 heterodimer binding to the broken DNA ends, followed by trimming via endonuclease Artemis and final ligation step via the LIG4‐XRCC4‐XLF‐PAXX complex. In MMEJ (sometimes also known as aEJ or TMEJ), PARP1 promotes DNA end synapsis and POLθ recruitment. After annealing of the microhomologous sequences (2–20 base pairs), the XPF/ERCC1 complex removes the redundant 3′ flaps. Subsequent ligation is mediated by LIG3/XRCC1. HR is initiated by DSB sensing by the MRN complex. Facilitated by BRCA1 and CtIP, MRN performs a short‐range resection, followed by a more extensive resection by EXO1 and/or BLM with DNA2 nuclease with subsequent coating of the 3’ ssDNA overhangs by RPA. BRCA1‐PALB2‐BRCA2 complex promotes RAD51 filament assembly. At this point, the DNA can be extended in a template‐dependent manner via SDSA, which results in a non‐crossover gene conversion. Alternatively, the formation of the double Holliday junction can resolve either as a crossover or as a non‐crossover. In contrast to MMEJ, SSA requires long regions of homology (20–25 base pairs) between the resected DNA ends. Annealing of the complementary ssDNA is mediated by RAD52, while non‐homologous flaps are digested by the XPF/ERCC1 complex. DSB, double‐strand break; 53BP1, p53 binding protein 1; BRCA1/2, breast cancer gene 1/2; NHEJ, non‐homologous end joining; HR, homologous recombination; LIG3/4, ligase 3/4; XRCC1/4, Xray repair cross‐complementing protein 1/4; XLF ‐ X‐ray repair cross‐complementing protein‐like factor; PAXX, paralogue of X‐ray repair cross‐complementing protein and X‐ray repair cross‐complementing protein‐like factor; MMEJ, microhomology‐mediated end joining; aEJ, alternative end joining; TMEJ, theta‐mediated end joining; PARP1, poly(ADP‐ribose) polymerase 1; POLθ, polymerase θ; XPF, xeroderma pigmentosum complementation group F; ERCC1 ‐ excision repair cross‐complementation group 1; DSB, double‐stranded break; MRN, meiotic recombination 11: radiation sensitive 50: Nijmegen breakage syndrome 1; CtIP, C‐terminal interacting protein; EXO1, exonuclease 1; BLM, Bloom syndrome helicase; DNA2, DNA replication helicase/nuclease 2; ssDNA, single‐stranded DNA; RPA, replication protein A; PALB2, partner and localiser of BRCA2; RAD51/52, radiation sensitive 51/52; SDSA, synthesis‐dependent strand annealing. [Colour figure can be viewed at wileyonlinelibrary.com]