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

By Sara Marie Ambjoern, Julien P Duxin, Emil PT Hertz, Isha Nasa, Joana Duro, Thomas Kruse, Blanca Lopez Mendez, Beata Rymarczyk, Lauren E Cressey, Thomas Hansen, Arminja Kettenbach, Vibe H Oestergaard, Michael Lisby, Jakob Nilsson

Posted 11 Apr 2021
bioRxiv DOI: 10.1101/2021.04.10.439193

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 promoting 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 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.

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