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A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination.
- Source :
-
Nature communications [Nat Commun] 2021 Sep 30; Vol. 12 (1), pp. 5748. Date of Electronic Publication: 2021 Sep 30. - Publication Year :
- 2021
-
Abstract
- Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers.<br /> (© 2021. The Author(s).)
- Subjects :
- BRCA2 Protein genetics
DNA Breaks, Double-Stranded
Female
Genetic Predisposition to Disease
HeLa Cells
Humans
Mutation
Phosphorylation genetics
Protein Binding genetics
Protein Phosphatase 2 genetics
Rad51 Recombinase metabolism
BRCA2 Protein metabolism
Breast Neoplasms genetics
Ovarian Neoplasms genetics
Protein Phosphatase 2 metabolism
Recombinational DNA Repair
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34593815
- Full Text :
- https://doi.org/10.1038/s41467-021-26079-0