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

Sara M Ambjørn, Julien P Duxin, Emil P T Hertz, Isha Nasa, Joana Duro, Thomas Kruse, Blanca Lopez-Mendez, Beata Rymarczyk, Lauren E Cressey, Thomas van Overeem Hansen, Arminja N Kettenbach, Vibe H Oestergaard, Michael Lisby, Jakob Nilsson

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.

OriginalsprogEngelsk
Artikelnummer5748
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Sider (fra-til)5748
ISSN2041-1722
DOI
StatusUdgivet - 30 sep. 2021

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