Geisel School of Medicine
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.
Ambjørn, S.M., Duxin, J.P., Hertz, E.P.T. et al. A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. Nat Commun 12, 5748 (2021). https://doi.org/10.1038/s41467-021-26079-0
Dartmouth Digital Commons Citation
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; and Nilsson, Jakob, "A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination" (2021). Dartmouth Scholarship. 4125.