BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

Zong, Dali; Adam, Salomé; Wang, Yifan; Sasanuma, Hiroyuki; Callén, Elsa; Murga, Matilde; Day, Amanda; Kruhlak, Michael J; Wong, Nancy; Munro, Meagan; Ray Chaudhuri, Arnab; Karim, Baktiar; Xia, Bing; Takeda, Shunichi; Johnson, Neil; Durocher, Daniel; Nussenzweig, André

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by...

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Autores:	Zong, Dali, Adam, Salomé, Wang, Yifan, Sasanuma, Hiroyuki, Callén, Elsa, Murga, Matilde, Day, Amanda, Kruhlak, Michael J, Wong, Nancy, Munro, Meagan, Ray Chaudhuri, Arnab, Karim, Baktiar, Xia, Bing, Takeda, Shunichi, Johnson, Neil, Durocher, Daniel, Nussenzweig, André
Formato:	artículo
Fecha de publicación:	2019
País:	España
Recursos:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/17692
Acesso em linha:	http://hdl.handle.net/20.500.12105/17692
Access Level:	acceso abierto
Palavra-chave:	Haploinsufficiency Ubiquitination Animals BRCA1 Protein BRCA2 Protein Cell Line, Tumor Chromatin DNA Damage Fanconi Anemia Complementation Group N Protein Female Fibroblasts Mice Mice, Inbred C57BL Mice, Knockout Mutation Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Recombinational DNA Repair Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases

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spelling	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.Zong, DaliAdam, SaloméWang, YifanSasanuma, HiroyukiCallén, ElsaMurga, MatildeDay, AmandaKruhlak, Michael JWong, NancyMunro, MeaganRay Chaudhuri, ArnabKarim, BaktiarXia, BingTakeda, ShunichiJohnson, NeilDurocher, DanielNussenzweig, AndréHaploinsufficiencyUbiquitinationAnimalsBRCA1 ProteinBRCA2 ProteinCell Line, TumorChromatinDNA DamageFanconi Anemia Complementation Group N ProteinFemaleFibroblastsMiceMice, Inbred C57BLMice, KnockoutMutationNeoplasmsPoly(ADP-ribose) Polymerase InhibitorsRad51 RecombinaseRecombinational DNA RepairTumor Suppressor p53-Binding Protein 1Ubiquitin-Protein LigasesBRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, and it predisposes BRCA1 heterozygous mice to cancer. BRCA1+/-RNF168-/- cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1 haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy for BRCA1-deficient cancers.Cell PressMinisterio de Educación, Cultura y Deporte (España)United States Department of Health and Human ServicesUnited States Department of DefenseNIH - National Cancer Institute (NCI) (Estados Unidos)Lawrence Ellison FoundationAlex's Lemonade Stand FoundationRutgers Cancer Institute20242024-02-0920192019-03-2120192019-03-21journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/17692reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/176922026-06-12T12:43:37Z
dc.title.none.fl_str_mv	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
title	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
spellingShingle	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation. Zong, Dali Haploinsufficiency Ubiquitination Animals BRCA1 Protein BRCA2 Protein Cell Line, Tumor Chromatin DNA Damage Fanconi Anemia Complementation Group N Protein Female Fibroblasts Mice Mice, Inbred C57BL Mice, Knockout Mutation Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Recombinational DNA Repair Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases
title_short	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
title_full	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
title_fullStr	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
title_full_unstemmed	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
title_sort	BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
dc.creator.none.fl_str_mv	Zong, Dali Adam, Salomé Wang, Yifan Sasanuma, Hiroyuki Callén, Elsa Murga, Matilde Day, Amanda Kruhlak, Michael J Wong, Nancy Munro, Meagan Ray Chaudhuri, Arnab Karim, Baktiar Xia, Bing Takeda, Shunichi Johnson, Neil Durocher, Daniel Nussenzweig, André
author	Zong, Dali
author_facet	Zong, Dali Adam, Salomé Wang, Yifan Sasanuma, Hiroyuki Callén, Elsa Murga, Matilde Day, Amanda Kruhlak, Michael J Wong, Nancy Munro, Meagan Ray Chaudhuri, Arnab Karim, Baktiar Xia, Bing Takeda, Shunichi Johnson, Neil Durocher, Daniel Nussenzweig, André
author_role	author
author2	Adam, Salomé Wang, Yifan Sasanuma, Hiroyuki Callén, Elsa Murga, Matilde Day, Amanda Kruhlak, Michael J Wong, Nancy Munro, Meagan Ray Chaudhuri, Arnab Karim, Baktiar Xia, Bing Takeda, Shunichi Johnson, Neil Durocher, Daniel Nussenzweig, André
author2_role	author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Ministerio de Educación, Cultura y Deporte (España) United States Department of Health and Human Services United States Department of Defense NIH - National Cancer Institute (NCI) (Estados Unidos) Lawrence Ellison Foundation Alex's Lemonade Stand Foundation Rutgers Cancer Institute
dc.subject.none.fl_str_mv	Haploinsufficiency Ubiquitination Animals BRCA1 Protein BRCA2 Protein Cell Line, Tumor Chromatin DNA Damage Fanconi Anemia Complementation Group N Protein Female Fibroblasts Mice Mice, Inbred C57BL Mice, Knockout Mutation Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Recombinational DNA Repair Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases
topic	Haploinsufficiency Ubiquitination Animals BRCA1 Protein BRCA2 Protein Cell Line, Tumor Chromatin DNA Damage Fanconi Anemia Complementation Group N Protein Female Fibroblasts Mice Mice, Inbred C57BL Mice, Knockout Mutation Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Recombinational DNA Repair Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases
description	BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, and it predisposes BRCA1 heterozygous mice to cancer. BRCA1+/-RNF168-/- cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1 haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy for BRCA1-deficient cancers.
publishDate	2019
dc.date.none.fl_str_mv	2019 2019-03-21 2019 2019-03-21 2024 2024-02-09
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/17692
url	http://hdl.handle.net/20.500.12105/17692
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Cell Press
publisher.none.fl_str_mv	Cell Press
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,811543

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

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