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dc.contributor.author | Ahuja, Akshay K | |
dc.contributor.author | Jodkowska, Karolina | |
dc.contributor.author | Teloni, Federico | |
dc.contributor.author | Bizard, Anna H | |
dc.contributor.author | Zellweger, Ralph | |
dc.contributor.author | Herrador, Raquel | |
dc.contributor.author | Ortega Jimenez, Sagrario | |
dc.contributor.author | Hickson, Ian D | |
dc.contributor.author | Altmeyer, Matthias | |
dc.contributor.author | Mendez, Juan | |
dc.contributor.author | Lopes, Massimo | |
dc.date.accessioned | 2019-07-08T09:13:24Z | |
dc.date.available | 2019-07-08T09:13:24Z | |
dc.date.issued | 2016-02-15 | |
dc.identifier.citation | Nat Commun. 2016 ;7:10660. | es_ES |
dc.identifier.issn | 2041-1723 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7866 | |
dc.description.abstract | Embryonic stem cells (ESCs) represent a transient biological state, where pluripotency is coupled with fast proliferation. ESCs display a constitutively active DNA damage response (DDR), but its molecular determinants have remained elusive. Here we show in cultured ESCs and mouse embryos that H2AX phosphorylation is dependent on Ataxia telangiectasia and Rad3 related (ATR) and is associated with chromatin loading of the ssDNA-binding proteins RPA and RAD51. Single-molecule analysis of replication intermediates reveals massive ssDNA gap accumulation, reduced fork speed and frequent fork reversal. All these marks of replication stress do not impair the mitotic process and are rapidly lost at differentiation onset. Delaying the G1/S transition in ESCs allows formation of 53BP1 nuclear bodies and suppresses ssDNA accumulation, fork slowing and reversal in the following S-phase. Genetic inactivation of fork slowing and reversal leads to chromosomal breakage in unperturbed ESCs. We propose that rapid cell cycle progression makes ESCs dependent on effective replication-coupled mechanisms to protect genome integrity. | es_ES |
dc.description.sponsorship | We thank the Center for Microscopy and Image Analysis of the University of Zurich and the Confocal Microscopy Unit and Transgenic Animal Unit (Biotechnology Programme,CNIO) for technical assistance. We are grateful to P. Cinelli and his group members fortechnical assistance in the initial phases of this project, and C. Santocanale, P. Schar,P. Janscak and A. Sartori for sharing reagents. We also thank S. Ferrari, P. Cinelli, L.Sommer, M. Manz and all current and past members of the Lopes group for usefuldiscussions. This work was supported by the Swiss National Science Foundation grants 31003A_146924 and PDFMP3_127523 to M.L. and grant PP00P3_150690/1 to M.A., bySAF2013–44866R (to S.O.) and BFU2013–49153-P grants from Spanish Ministry of Economy and Competitiveness (MINECO) to J.M., and by the European Research Council, Nordea Foundation and Danish National Research Foundation to I.D.H | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Ataxia Telangiectasia Mutated Proteins | es_ES |
dc.subject.mesh | Blastocyst | es_ES |
dc.subject.mesh | Blotting, Western | es_ES |
dc.subject.mesh | Chromatin | es_ES |
dc.subject.mesh | Chromosomal Proteins, Non-Histone | es_ES |
dc.subject.mesh | DNA, Single-Stranded | es_ES |
dc.subject.mesh | DNA-Binding Proteins | es_ES |
dc.subject.mesh | Electrophoresis, Gel, Pulsed-Field | es_ES |
dc.subject.mesh | Flow Cytometry | es_ES |
dc.subject.mesh | Histones | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Microscopy, Confocal | es_ES |
dc.subject.mesh | Microscopy, Electron | es_ES |
dc.subject.mesh | Microscopy, Fluorescence | es_ES |
dc.subject.mesh | Mitosis | es_ES |
dc.subject.mesh | Morula | es_ES |
dc.subject.mesh | Mouse Embryonic Stem Cells | es_ES |
dc.subject.mesh | Phosphorylation | es_ES |
dc.subject.mesh | Poly(ADP-ribose) Polymerases | es_ES |
dc.subject.mesh | Rad51 Recombinase | es_ES |
dc.subject.mesh | Replication Protein A | es_ES |
dc.subject.mesh | Tumor Suppressor p53-Binding Protein 1 | es_ES |
dc.subject.mesh | DNA Damage | es_ES |
dc.subject.mesh | DNA Replication | es_ES |
dc.subject.mesh | G1 Phase | es_ES |
dc.subject.mesh | G1 Phase Cell Cycle Checkpoints | es_ES |
dc.title | A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 26876348 | es_ES |
dc.format.volume | 7 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 10660 | es_ES |
dc.identifier.doi | 10.1038/ncomms10660 | es_ES |
dc.contributor.funder | Danish National Research Foundation | |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2041-1723 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/ncomms10660. | es_ES |
dc.identifier.journal | Nature communications | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Replicación de ADN | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2013–44866R | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BFU2013–49153-P | es_ES |
dc.rights.accessRights | open access | es_ES |