PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

Rimma Belotserkovskaya; Elisenda Raga Gil; Nicola Lawrence; Richard Butler; Gillian Clifford; Marcus D. Wilson; Stephen P. Jackson

doi:10.1038/s41467-020-14563-y

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

Rimma Belotserkovskaya (Lead / Corresponding author), Elisenda Raga Gil, Nicola Lawrence, Richard Butler, Gillian Clifford, Marcus D. Wilson (Lead / Corresponding author), Stephen P. Jackson (Lead / Corresponding author)

Gene Regulation and Expression

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

71 Downloads (Pure)

Abstract

Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.

Original language	English
Article number	819
Pages (from-to)	1-11
Number of pages	11
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-14563-y
Publication status	Published - 10 Feb 2020

Keywords

Cellular imaging
Homologous recombination

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-020-14563-yLicence: CC BY

Final Published VersionFinal published version, 1.7 MBLicence: CC BY

Cite this

@article{f371ea63450542fd8a99e064b0886373,

title = "PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1",

abstract = "Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.",

keywords = "Cellular imaging, Homologous recombination",

author = "Rimma Belotserkovskaya and {Raga Gil}, Elisenda and Nicola Lawrence and Richard Butler and Gillian Clifford and Wilson, {Marcus D.} and Jackson, {Stephen P.}",

note = "We are very grateful to Alessandro Costa (Crick Research Institute) for supporting M.D.W. during the initiation of the project. The S.P.J. lab is funded by the Cancer Research UK (CRUK) Program Grant C6/A18796, and Wellcome Investigator Award 206388/Z/17/Z. Core infrastructure funding was provided by CRUK Grant C6946/A24843 and Wellcome Grant WT203144. S.P.J. receives salary from the University of Cambridge. R.B. is funded by CRUK Program Grant C6/A18796, E.R.-G. is funded by Action for A-T and the A-T Children{\textquoteright}s Project. M.D.W.{\textquoteright}s work is supported by Wellcome [210493] and the University of Edinburgh. The Wellcome Centre for Cell Biology is supported by core funding from Wellcome [203149] and Multi-User Equipment grant [101527] for the Edinburgh Protein Production Facility.",

year = "2020",

month = feb,

day = "10",

doi = "10.1038/s41467-020-14563-y",

language = "English",

volume = "11",

pages = "1--11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

AU - Belotserkovskaya, Rimma

AU - Raga Gil, Elisenda

AU - Lawrence, Nicola

AU - Butler, Richard

AU - Clifford, Gillian

AU - Wilson, Marcus D.

AU - Jackson, Stephen P.

N1 - We are very grateful to Alessandro Costa (Crick Research Institute) for supporting M.D.W. during the initiation of the project. The S.P.J. lab is funded by the Cancer Research UK (CRUK) Program Grant C6/A18796, and Wellcome Investigator Award 206388/Z/17/Z. Core infrastructure funding was provided by CRUK Grant C6946/A24843 and Wellcome Grant WT203144. S.P.J. receives salary from the University of Cambridge. R.B. is funded by CRUK Program Grant C6/A18796, E.R.-G. is funded by Action for A-T and the A-T Children’s Project. M.D.W.’s work is supported by Wellcome [210493] and the University of Edinburgh. The Wellcome Centre for Cell Biology is supported by core funding from Wellcome [203149] and Multi-User Equipment grant [101527] for the Edinburgh Protein Production Facility.

PY - 2020/2/10

Y1 - 2020/2/10

N2 - Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.

AB - Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.

KW - Cellular imaging

KW - Homologous recombination

UR - http://www.scopus.com/inward/record.url?scp=85079214684&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14563-y

DO - 10.1038/s41467-020-14563-y

M3 - Article

C2 - 32041954

SN - 2041-1723

VL - 11

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

M1 - 819

ER -

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this