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 () and Jakob Nilsson ()
Additional contact information
Sara M. Ambjørn: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Julien P. Duxin: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Emil P. T. Hertz: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Isha Nasa: Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College
Joana Duro: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Thomas Kruse: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Blanca Lopez-Mendez: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Beata Rymarczyk: University of Konstanz
Lauren E. Cressey: Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College
Thomas van Overeem Hansen: Copenhagen University Hospital, Rigshospitalet
Arminja N. Kettenbach: Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College
Vibe H. Oestergaard: University of Copenhagen
Michael Lisby: University of Copenhagen
Jakob Nilsson: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26079-0

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