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In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

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dc.contributor.authorMuñoz, Sergio
dc.contributor.authorBúa, Sabela
dc.contributor.authorRodriguez-Acebes, Sara
dc.contributor.authorMegias Vazquez, Diego
dc.contributor.authorOrtega Jimenez, Sagrario
dc.contributor.authorde Martino, Alba
dc.contributor.authorMendez, Juan
dc.contributor.funderMinisterio de Ciencia y Competitividad (España)
dc.date.accessioned2019-02-25T12:12:50Z
dc.date.available2019-02-25T12:12:50Z
dc.date.issued2017
dc.description.abstractMammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Here, we have generated mice strains that allow the conditional overexpression of both proteins. Adult mice were unharmed by the individual overexpression of either CDC6 or CDT1, but their combined deregulation led to DNA re-replication in progenitor cells and lethal tissue dysplasias. This study offers mechanistic insights into the necessary cooperation between CDC6 and CDT1 for facilitation of origin reactivation and describes the physiological consequences of DNA overreplication.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe thank all members of the DNA Replication and Chromosome Dynamics Groups for discussions, S. Ruiz and I. Blanco for their help with mouse work, B. Urcelay for technical support, M. Udriste for assistance with IHC quantifications, U. Cronin and D. Martınezfor assistance with flow cytometryexperiments, M. Canamero for the initial histopathology analyses, and O. Fernandez-Capetillo for comments on the manuscript. Research was supported by MINECO grants BFU2013-49153-P, BFU2016-80402-R, and CSD2007- 00015 to J.M. and MINECO predoctoral fellowships to S.M. and S.Bes_ES
dc.format.number5es_ES
dc.format.page928-938es_ES
dc.format.volume19es_ES
dc.identifier.citationCell Rep. 2017 ;19(5):928-938.es_ES
dc.identifier.doi10.1016/j.celrep.2017.04.032es_ES
dc.identifier.e-issn2211-1247es_ES
dc.identifier.issn22111247es_ES
dc.identifier.journalCell reportses_ES
dc.identifier.pubmedID28467906es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7230
dc.language.isoenges_ES
dc.publisherElsevier
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2013-49153-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2016-80402-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CSD2007-00015es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.celrep.2017.04.032.es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Dinámica Cromosómicaes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCDC6es_ES
dc.subjectCDT1es_ES
dc.subjectDNA replicationes_ES
dc.subjectReplication origines_ES
dc.subjectTIssue dysplasiaes_ES
dc.subject.meshAnimalses_ES
dc.subject.meshCell Cycle Proteinses_ES
dc.subject.meshDNA-Binding Proteinses_ES
dc.subject.meshDiarrhea, Infantilees_ES
dc.subject.meshFemalees_ES
dc.subject.meshIntestinal Mucosaes_ES
dc.subject.meshMalabsorption Syndromeses_ES
dc.subject.meshMalees_ES
dc.subject.meshMicees_ES
dc.subject.meshNuclear Proteinses_ES
dc.subject.meshTransgeneses_ES
dc.subject.meshDNA Replicationes_ES
dc.titleIn Vivo DNA Re-replication Elicits Lethal Tissue Dysplasiases_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
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