A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. / Ambjorn, 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.
I: Nature Communications, Bind 12, Nr. 1, 5748, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination
AU - Ambjorn, Sara M.
AU - Duxin, Julien P.
AU - Hertz, Emil P. T.
AU - Nasa, Isha
AU - Duro, Joana
AU - Kruse, Thomas
AU - Lopez-Mendez, Blanca
AU - Rymarczyk, Beata
AU - Cressey, Lauren E.
AU - van Overeem Hansen, Thomas
AU - Kettenbach, Arminja N.
AU - Oestergaard, Vibe H.
AU - Lisby, Michael
AU - Nilsson, Jakob
PY - 2021
Y1 - 2021
N2 - 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.BRCA2 plays a central role in facilitating DNA repair by homologous recombination (HR). Here the authors describe how BRCA2 forms a complex with the protein phosphatase PP2A-B56 in response to DNA damage, which is required for HR.
AB - 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.BRCA2 plays a central role in facilitating DNA repair by homologous recombination (HR). Here the authors describe how BRCA2 forms a complex with the protein phosphatase PP2A-B56 in response to DNA damage, which is required for HR.
KW - CROSS-LINK
KW - GENOME INTEGRITY
KW - DIRECTED REPAIR
KW - REPLICATION
KW - RAD51
KW - BREAST
KW - PROMOTES
KW - MECHANISM
KW - PHOSPHORYLATION
KW - DEGRADATION
U2 - 10.1038/s41467-021-26079-0
DO - 10.1038/s41467-021-26079-0
M3 - Journal article
C2 - 34593815
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5748
ER -
ID: 281705349