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

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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.

In: Nature Communications, Vol. 12, No. 1, 5748, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ambjorn, SM, Duxin, JP, Hertz, EPT, Nasa, I, Duro, J, Kruse, T, Lopez-Mendez, B, Rymarczyk, B, Cressey, LE, van Overeem Hansen, T, Kettenbach, AN, Oestergaard, VH, Lisby, M & Nilsson, J 2021, 'A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination', Nature Communications, vol. 12, no. 1, 5748. https://doi.org/10.1038/s41467-021-26079-0

APA

Ambjorn, S. M., Duxin, J. P., Hertz, E. P. T., Nasa, I., Duro, J., Kruse, T., Lopez-Mendez, B., Rymarczyk, B., Cressey, L. E., van Overeem Hansen, T., Kettenbach, A. N., Oestergaard, V. H., Lisby, M., & Nilsson, J. (2021). A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. Nature Communications, 12(1), [5748]. https://doi.org/10.1038/s41467-021-26079-0

Vancouver

Ambjorn SM, Duxin JP, Hertz EPT, Nasa I, Duro J, Kruse T et al. A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. Nature Communications. 2021;12(1). 5748. https://doi.org/10.1038/s41467-021-26079-0

Author

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. / A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{bc807dfcb83a4d1a89e2958ba27e0a6b,
title = "A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination",
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.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.",
keywords = "CROSS-LINK, GENOME INTEGRITY, DIRECTED REPAIR, REPLICATION, RAD51, BREAST, PROMOTES, MECHANISM, PHOSPHORYLATION, DEGRADATION",
author = "Ambjorn, {Sara M.} and Duxin, {Julien P.} and Hertz, {Emil P. T.} and Isha Nasa and Joana Duro and Thomas Kruse and Blanca Lopez-Mendez and Beata Rymarczyk and Cressey, {Lauren E.} and {van Overeem Hansen}, Thomas and Kettenbach, {Arminja N.} and Oestergaard, {Vibe H.} and Michael Lisby and Jakob Nilsson",
year = "2021",
doi = "10.1038/s41467-021-26079-0",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

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