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

Stable Identifier
R-HSA-9701190
DOI
10.3180/R-HSA-9701190.1
Type
Pathway
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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Defective homologous recombination repair (HRR) due to BRCA2 loss of function
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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.
Literature References
PubMed ID Title Journal Year
34522048 Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Gupta, GP, Carvajal-Garcia, J, Ramsden, DA

Nat Rev Mol Cell Biol 2022
29376519 Fanconi anaemia and cancer: an intricate relationship

Clapp, DW, Nalepa, G

Nat Rev Cancer 2018
22193408 BRCA1 and BRCA2: different roles in a common pathway of genome protection

Powell, SN, Roy, R, Chun, J

Nat. Rev. Cancer 2011
31337537 How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility?

Venkitaraman, AR

DNA Repair (Amst) 2019
34616021 Delayed DNA break repair for genome stability

Petropoulos, M, Halazonetis, TD

Nat Cell Biol 2021
34440403 Guardians of the Genome: BRCA2 and Its Partners

Heyer, WD, Le, HP, Liu, J

Genes (Basel) 2021
30453575 Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

Stoppa-Lyonnet, D, Burke, L, Lallemand, F, Caputo, SM, Rouleau, E, Brown, M, Santana Dos Santos, E

Cancers (Basel) 2018
35419469 Turning end-joining upside down in mitosis

Heyer, WD, Lobrich, M, Le, HP, Llorens-Agost, M, Ensminger, M

Mol Cell Oncol 2021
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Orlic-Milacic, M  (2020-12-11)
Reviewed
Liu, J  (2022-01-26)
Le, HP  (2022-01-26)
Heyer, WD  (2022-01-26)
Created
Orlic-Milacic, M  (2020-09-24)
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