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

Ambjoern, S. M.; Duxin, J. P.; Hertz, E. P.; Nasa, I.; Duro, J.; Kruse, T.; Lopez Mendez, B.; Rymarczyk, B.; Cressey, L. E.; Hansen, T.; Kettenbach, A.; Oestergaard, V. H.; Lisby, M.; Nilsson, J.

doi:10.1101/2021.04.10.439193

bioRxiv · 10.1101/2021.04.10.439193

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

Ambjoern, S. M.·Duxin, J. P.·Hertz, E. P.·Nasa, I.·Duro, J.·Kruse, T.·Lopez Mendez, B.·Rymarczyk, B.·Cressey, L. E.·Hansen, T.·Kettenbach, A.·Oestergaard, V. H.·Lisby, M.·Nilsson, J.

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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 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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Ambjoern, S. M., Duxin, J. P., Hertz, E. P., Nasa, I., Duro, J., Kruse, T., Lopez Mendez, B., Rymarczyk, B., Cressey, L. E., Hansen, T., Kettenbach, A., Oestergaard, V. H., Lisby, M., Nilsson, J.. 2021-04-11. A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. https://doi.org/10.1101/2021.04.10.439193

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