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dc.contributor.authorSedic, Maja
dc.contributor.authorSkibinski, Adam
dc.contributor.authorBrown, Nelson
dc.contributor.authorGallardo, Mercedes
dc.contributor.authorMulligan, Peter
dc.contributor.authorMartinez Rodriguez, Paula 
dc.contributor.authorKeller, Patricia J
dc.contributor.authorGlover, Eugene
dc.contributor.authorRichardson, Andrea L
dc.contributor.authorCowan, Janet
dc.contributor.authorToland, Amanda E
dc.contributor.authorRavichandran, Krithika
dc.contributor.authorRiethman, Harold
dc.contributor.authorNaber, Stephen P
dc.contributor.authorNäär, Anders M
dc.contributor.authorBlasco, MA 
dc.contributor.authorHinds, Philip W
dc.contributor.authorKuperwasser, Charlotte
dc.date.accessioned2020-05-08T16:29:23Z
dc.date.available2020-05-08T16:29:23Z
dc.date.issued2015-06-24
dc.identifier.citationNat Commun. 2015;6:7505.es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/10004
dc.description.abstractAlthough BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.es_ES
dc.description.sponsorshipThis work was supported by grants from the Raymond and Beverly Sackler Foundation (M.S.), the Breast Cancer Research Foundation (B.K. and C.K.), the Silvian Foundation (C.K. and A.S.) and the NIH/NCI CA125554 (C.K.), CA092644 (C.K.). Research in the Blasco laboratory was funded by ERC Project Project TEL STEM CELL, FP7 Projects MARK-AGE and EuroBATS, Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, Regional of Government of Madrid Project S2010/BMD-2303, AXA Research Fund, Fundacion Botin (Spain) and Fundacion Lilly (Spain). We thank members of the Kuperwasser laboratory for valuable discussions as well as Benjamin Dake, Sarah Phillips and Agueda Tejera for their help with experiments.es_ES
dc.language.isoenges_ES
dc.publisherNATURE PUBLISHING GROUPes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshCellular Senescence es_ES
dc.subject.meshDNA Damage es_ES
dc.subject.meshEpithelial Cells es_ES
dc.subject.meshGenomic Instability es_ES
dc.subject.meshHeterozygote es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMammary Glands, Humanes_ES
dc.subject.meshMutation es_ES
dc.subject.meshRetinoblastoma Protein es_ES
dc.subject.meshSirtuin 1 es_ES
dc.subject.meshTelomere Shortening es_ES
dc.subject.meshTumor Suppressor Protein p53 es_ES
dc.subject.meshGenes, BRCA1 es_ES
dc.subject.meshHaploinsufficiency es_ES
dc.titleHaploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescencees_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID26106036es_ES
dc.format.volume6es_ES
dc.format.number1es_ES
dc.format.page7505es_ES
dc.identifier.doi10.1038/ncomms8505es_ES
dc.contributor.funderRaymond and Beverly Sackler Foundationes_ES
dc.contributor.funderBreast Cancer Research Foundationes_ES
dc.contributor.funderSilvian Foundationes_ES
dc.contributor.funderNIH National Cancer Institute (NCI)es_ES
dc.contributor.funderEuropean Research Council (ERC)es_ES
dc.contributor.funderMinisterio de Economia y Competitividades_ES
dc.contributor.funderAXA Research Fundes_ES
dc.contributor.funderFundacion Botin (Spain)es_ES
dc.contributor.funderFundacion Lilly (Spain)es_ES
dc.contributor.funderComunidad de Madrides_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-1723es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/ncomms8505.es_ES
dc.identifier.journalNature communicationses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Telómeros y Telomerasaes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2008-05384es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/CSD2007-00017es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
This item is licensed under a: Atribución-NoComercial-CompartirIgual 4.0 Internacional