Defective homologous recombination repair (HRR) due to BRCA2 loss of function

Besides its crucial role in HRR, BRCA2 is also implicated in protection of replication forks, centrosome duplication, spindle assembly checkpoint and cytokinesis. Recently published studies show the involvement of BRCA2 in the turnover of R-loops (hybrids between RNA and single strand DNA that are generated as intermediates of gene transcription). Unscheduled accumulated R-loops may be processed into DSBs, leading to genomic instability. Finally, BRCA2 is involved in pathway choice of DSB repair by inhibiting DNA polymerase theta-mediated end-joining (TMEJ) until M-phase (reviewed in Petropoulos and Halazonetis 2021, and Llorens-Agost et al. 2021). TMEJ is the predominant pathway for microhomology-mediated end joining MMEJ/alternative-nonhomologous end joining (alt-NHEJ, a-EJ) in mammals (reviewed in Ramsden et al. 2022).

BRCA2 haploinsufficiency is frequently observed in cancers, with close to 50% of BRCA2-mutant breast cancers retaining one wild type allele, suggesting that in some tissues at least heterozygous loss of BRCA2 function is sufficient for carcinogenesis. Promoter hypermethylation is not an obvious contributor to BRCA2 gene inactivation and no pathogenic mutations in the promoter region have been identified so far.

For review, please refer to Roy et al. 2011, Nalepa and Clapp 2018, Santana dos Santos et al. 2018, Venkitaraman 2019, Le et al. 2021, and Llorens-Agost et al. 2021.