BRCA2 mutants with BRC defects or a defect in the C-terminal RAD51 binding site do not bind RAD51

Stable Identifier
R-HSA-9709571
Type
Reaction [transition]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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BRCA2 mutants with BRC defects or a defect in the C-terminal RAD51 binding site do not bind RAD51
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BRCA2 contains 8 BRC repeats in its middle region, which are involved in binding to RAD51 at resected DNA double-strand breaks (DSBs) (Bork et al. 1996, Wong et al. 1997, Venkitaraman 2002). Some BRCA2 missense mutations reported in cancer have been shown to impair BRCA2 binding to RAD51.

BRCA2 G1529R mutant, involved in familial breast cancer, has a missense mutation that affects the fourth BRC repeat of BRCA2 (BRC4). The BRC4 construct which harbors the G1529R substitution shows 20-fold reduced binding to RAD51 relative to the wild type BRC4 (Chen et al. 1999). CHEK1 phosphorylation sites are preserved in BRCA2 G1529R mutant, but the phosphorylation is not shown as it has not been tested.
BRCA2 mutant BRCA2 G1529E is annotated as candidate mutant for the loss of RAD51 binding as it has been reported in cancer, is predicted to be pathogenic and involves the same amino acid residue as the functionally characterized BRCA2 G1529R mutant.

The C-terminal RAD51 interaction site, TR2, binds to RAD51 filaments and protects them from disassembly (Davies et al. 2007). TR2 is essential for the replication fork stabilization function of BRCA2 but dispensable for homology-directed repair (Schlacher et al. 2011). BRCA2 S3291A mutant, generated by directed mutagenesis, is unable to bind to RAD51. This mutant has not been reported in cancer but is documented as a BRCA2 allele in the ClinGen Allele Registry (Pawliczek et al. 2018).
Literature References
PubMed ID Title Journal Year
10551859 Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control

Sharp, ZD, Lee, WH, Zhong, Q, Chen, CF, Chen, PL

J Biol Chem 1999
17515903 Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats

Pellegrini, L, Davies, OR

Nat Struct Mol Biol 2007
21565612 Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11

Siaud, N, Christ, N, Jasin, M, Wu, H, Egashira, A, Schlacher, K

Cell 2011
Participants
Input
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as an event of
Normal reaction
RAD51 binds BRCA2 at resected DNA DSBs (Homo sapiens)
Functional status

Loss of function of BRCA2 mutants (RAD51 binding):SEM1 [nucleoplasm]

Normal Entity
Disease Entity
Status
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  (2020-12-15)
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