BRCA2 (FANCD1) is a tumor suppressor gene located on chromosomal arm 13q. BRCA2 protein is a mediator of the core mechanism of homologous recombination repair (HRR), essential for the recruitment of RAD51 recombinase to resected DNA double-strand breaks (DSBs). Monoallelic pathogenic germline mutations in BRCA2 are one of the underlying causes of the hereditary breast and ovarian cancer (HBOC) syndrome, with carriers having close to 50% lifetime risk for development of breast cancer and about 15% lifetime risk for development of ovarian cancer. In addition, BRCA2 germline mutation carriers are predisposed to cancers of the fallopian tube, pancreas, stomach, larynx and prostate. Biallelic germline mutations in BRCA2 cause Fanconi anemia subtype characterized by brain and soft tissue tumors, including medulloblastoma and Wilms tumor. BRCA2-deficient cells are defective in the formation of RAD51 foci upon treatment with DSB-inducing DNA damaging agents and accumulate chromatid breaks and radial chromosomes.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.
Santana Dos Santos, E