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dc.contributor.authorRuiz, Sergio
dc.contributor.authorMayor-Ruiz, Cristina 
dc.contributor.authorLafarga, Vanesa 
dc.contributor.authorMurga M, Matilde 
dc.contributor.authorVega-Sendino, Maria
dc.contributor.authorOrtega Jimenez, Sagrario 
dc.contributor.authorFernandez-Capetillo, Oscar 
dc.date.accessioned2019-10-23T08:56:27Z
dc.date.available2019-10-23T08:56:27Z
dc.date.issued2016-04-21
dc.identifier.citationMol Cell. 2016;62(2):307-313.es_ES
dc.identifier.issn10972765es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8526
dc.description.abstractOne recurring theme in drug development is to exploit synthetic lethal properties as means to preferentially damage the DNA of cancer cells. We and others have previously developed inhibitors of the ATR kinase, shown to be particularly genotoxic for cells expressing certain oncogenes. In contrast, the mechanisms of resistance to ATR inhibitors remain unexplored. We report here on a genome-wide CRISPR-Cas9 screen that identified CDC25A as a major determinant of sensitivity to ATR inhibition. CDC25A-deficient cells resist high doses of ATR inhibitors, which we show is due to their failure to prematurely enter mitosis in response to the drugs. Forcing mitotic entry with WEE1 inhibitors restores the toxicity of ATR inhibitors in CDC25A-deficient cells. With ATR inhibitors now entering the clinic, our work provides a better understanding of the mechanisms by which these compounds kill cells and reveals genetic interactions that could be used for their rational use.es_ES
dc.description.sponsorshipWe thank the laboratories of Feng Zhang and Kosuke Yusa for sharing all CRISPR-related plasmids used here through Addgene (plasmids 42230, 50946, and 50947) and Edna Fonseca for her comments on the manuscript. Research was funded by Fundacion Botin, Banco Santander, through its Santander Universities Global Division and by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2011-23753 and SAF2014-57791-REDC), Fundacio La Marato de TV3, the Howard Hughes Medical Institute, and the European Research Council (ERC-617840) to O.F.-C.; by a PhD fellowship from La Caixa Foundation to C.M.-R.; by grants from MINECO to S.R. (RYC2011-09242 and SAF2013-49147P, this last project co-financed with European FEDER funds); and by a grant from MINECO (SAF2013-44866-R) to S.O.es_ES
dc.language.isoenges_ES
dc.publisherCell Presses_ES
dc.relation.isversionofPostprintes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAntineoplastic Agents es_ES
dc.subject.meshAtaxia Telangiectasia Mutated Proteins es_ES
dc.subject.meshCell Cycle Proteins es_ES
dc.subject.meshCell Line es_ES
dc.subject.meshDose-Response Relationship, Druges_ES
dc.subject.meshDrug Resistance, Neoplasm es_ES
dc.subject.meshEmbryonic Stem Cells es_ES
dc.subject.meshGenome-Wide Association Study es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMitosis es_ES
dc.subject.meshMolecular Targeted Therapy es_ES
dc.subject.meshNuclear Proteins es_ES
dc.subject.meshProtein Kinase Inhibitors es_ES
dc.subject.meshProtein-Tyrosine Kinases es_ES
dc.subject.meshRNA Interference es_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshTransfection es_ES
dc.subject.meshcdc25 Phosphatases es_ES
dc.subject.meshCRISPR-Cas Systems es_ES
dc.titleA Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitorses_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID27067599es_ES
dc.format.volume62es_ES
dc.format.number2es_ES
dc.format.page307-313es_ES
dc.identifier.doi10.1016/j.molcel.2016.03.006es_ES
dc.contributor.funderFundacion Botines_ES
dc.contributor.funderMinisterio de Economia y Competitividad (España)es_ES
dc.contributor.funderFundacion La Mataroes_ES
dc.contributor.funderHoward Hughes Medical Institutees_ES
dc.contributor.funderEuropean Research Council (ERC)es_ES
dc.contributor.funderFundación La Caixaes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1097-4164es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.molcel.2016.03.006.es_ES
dc.identifier.journalMolecular celles_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Inestabilidad Genómicaes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2011-23753es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2014-57791-REDCes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/RYC2011-09242es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2013-49147Pes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2013-44866-Res_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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