dc.contributor.author | Ruiz, Sergio | |
dc.contributor.author | Mayor-Ruiz, Cristina | |
dc.contributor.author | Lafarga, Vanesa | |
dc.contributor.author | Murga, Matilde | |
dc.contributor.author | Vega-Sendino, Maria | |
dc.contributor.author | Ortega Jimenez, Sagrario | |
dc.contributor.author | Fernandez-Capetillo, Oscar | |
dc.date.accessioned | 2019-10-23T08:56:27Z | |
dc.date.available | 2019-10-23T08:56:27Z | |
dc.date.issued | 2016-04-21 | |
dc.identifier.citation | Mol Cell. 2016;62(2):307-313. | es_ES |
dc.identifier.issn | 10972765 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/8526 | |
dc.description.abstract | One 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.sponsorship | We 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.iso | eng | es_ES |
dc.publisher | Cell Press | es_ES |
dc.type.hasVersion | AM | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Antineoplastic Agents | es_ES |
dc.subject.mesh | Ataxia Telangiectasia Mutated Proteins | es_ES |
dc.subject.mesh | Cell Cycle Proteins | es_ES |
dc.subject.mesh | Cell Line | es_ES |
dc.subject.mesh | Dose-Response Relationship, Drug | es_ES |
dc.subject.mesh | Drug Resistance, Neoplasm | es_ES |
dc.subject.mesh | Embryonic Stem Cells | es_ES |
dc.subject.mesh | Genome-Wide Association Study | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mitosis | es_ES |
dc.subject.mesh | Molecular Targeted Therapy | es_ES |
dc.subject.mesh | Nuclear Proteins | es_ES |
dc.subject.mesh | Protein Kinase Inhibitors | es_ES |
dc.subject.mesh | Protein-Tyrosine Kinases | es_ES |
dc.subject.mesh | RNA Interference | es_ES |
dc.subject.mesh | Signal Transduction | es_ES |
dc.subject.mesh | Transfection | es_ES |
dc.subject.mesh | cdc25 Phosphatases | es_ES |
dc.subject.mesh | CRISPR-Cas Systems | es_ES |
dc.title | A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 27067599 | es_ES |
dc.format.volume | 62 | es_ES |
dc.format.number | 2 | es_ES |
dc.format.page | 307-313 | es_ES |
dc.identifier.doi | 10.1016/j.molcel.2016.03.006 | es_ES |
dc.contributor.funder | Botín Foundation | |
dc.contributor.funder | Fundación La Marató TV3 | |
dc.contributor.funder | Howard Hughes Medical Institute | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.contributor.funder | Fundación La Caixa | |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1097-4164 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1016/j.molcel.2016.03.006. | es_ES |
dc.identifier.journal | Molecular cell | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Inestabilidad Genómica | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2011-23753 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2014-57791-REDC | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/RYC2011-09242 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2013-49147P | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2013-44866-R | es_ES |
dc.rights.accessRights | open access | es_ES |