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A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination.
Ambjørn, Sara M; Duxin, Julien P; Hertz, Emil P T; Nasa, Isha; Duro, Joana; Kruse, Thomas; Lopez-Mendez, Blanca; Rymarczyk, Beata; Cressey, Lauren E; van Overeem Hansen, Thomas; Kettenbach, Arminja N; Oestergaard, Vibe H; Lisby, Michael; Nilsson, Jakob.
Afiliación
  • Ambjørn SM; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Duxin JP; Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Hertz EPT; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Nasa I; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Duro J; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Dartmouth, NH, USA.
  • Kruse T; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Lopez-Mendez B; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Rymarczyk B; The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Cressey LE; Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
  • van Overeem Hansen T; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Dartmouth, NH, USA.
  • Kettenbach AN; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
  • Oestergaard VH; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Dartmouth, NH, USA.
  • Lisby M; Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark. vibe@bio.ku.dk.
  • Nilsson J; Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark. mlisby@bio.ku.dk.
Nat Commun ; 12(1): 5748, 2021 09 30.
Article en En | MEDLINE | ID: mdl-34593815
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Neoplasias de la Mama / Proteína BRCA2 / Proteína Fosfatasa 2 / Reparación del ADN por Recombinación Límite: Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Neoplasias de la Mama / Proteína BRCA2 / Proteína Fosfatasa 2 / Reparación del ADN por Recombinación Límite: Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido