MassIVE MSV000087884

Complete Public PXD027574

A complex of BRCA2 and PP2A-B56 is required for homologous recombination-mediated DNA repair

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Description

Mutations in the tumour suppressor BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination. BRCA2 acts by promoting RAD51 nucleofilament 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 DNA 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 loading to 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. [doi:10.25345/C5SR9N] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: BRCA2 ; cancer ; breast ; ovarian ; DSB ; homologous recombination ; RAD51 ; HR ; ATM ; ATR ; kinase ; PP2A-B56 ; PARP

Contact

Principal Investigators:
(in alphabetical order) 		Arminja Kettenbach, The Geisel School of Medicine at Dartmouth, United States
Submitting User: madamo
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