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dc.contributor.author | Ibarra, Arkaitz | |
dc.contributor.author | Schwob, Etienne | |
dc.contributor.author | Mendez, Juan | |
dc.date.accessioned | 2024-02-08T20:15:01Z | |
dc.date.available | 2024-02-08T20:15:01Z | |
dc.date.issued | 2008-07-01 | |
dc.identifier.citation | Proc Natl Acad Sci U S A . 2008 ;105(26):8956-61 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/17664 | |
dc.description.abstract | The six main minichromosome maintenance proteins (Mcm2-7), which presumably constitute the core of the replicative DNA helicase, are present in chromatin in large excess relative to the number of active replication forks. To evaluate the relevance of this apparent surplus of Mcm2-7 complexes in human cells, their levels were down-regulated by using RNA interference. Interestingly, cells continued to proliferate for several days after the acute (>90%) reduction of Mcm2-7 concentration. However, they became hypersensitive to DNA replication stress, accumulated DNA lesions, and eventually activated a checkpoint response that prevented mitotic division. When this checkpoint was abrogated by the addition of caffeine, cells quickly lost viability, and their karyotypes revealed striking chromosomal aberrations. Single-molecule analyses revealed that cells with a reduced concentration of Mcm2-7 complexes display normal fork progression but have lost the potential to activate "dormant" origins that serve a backup function during DNA replication. Our data show that the chromatin-bound "excess" Mcm2-7 complexes play an important role in maintaining genomic integrity under conditions of replicative stress. | es_ES |
dc.description.sponsorship | We are grateful to A. Losada, O. Ferna´ ndez-Capetillo, and members of the J.M. laboratory for critically reading the manuscript; V. Coulon and the Montpellier DNA Combing Facility for help with single- molecule analyses; J. C. Cigudosa and the Spanish National Cancer Research Centre (CNIO) Cytogenetics Unit for the metaphase spread analyses; and D. Megı´as and the CNIO Confocal Microscopy Unit for assistance with Meta- 8960 www.pnas.org cgi doi 10.1073 pnas.0803978105 Ibarra et al.Downloaded from https://www.pnas.org by Centro Nacional de Investigaciones Oncologicas CNIO on February 8, 2024 from IP address 193.147.150.204. morph 7. This work was supported by Spanish Ministry of Education and Science Grants BFU2004-04886 and CSD2007-0015, European Community Marie Curie International Reintegration Grant FP6-031129, and a Fundacio´ n Caja Madrid grant (to J.M.) and Institut National du Cancer Grant PL110 and Association pour la Recherche sur le Cancer Grant SL3149 (to E.S.). A.I. was supported by a predoctoral fellowship from the Basque Government. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | National Academy of Sciences | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | DNA Replication | es_ES |
dc.subject.mesh | Replication Origin | es_ES |
dc.subject.mesh | Cell Proliferation | es_ES |
dc.subject.mesh | Chromosomal Instability | es_ES |
dc.subject.mesh | DNA Damage | es_ES |
dc.subject.mesh | HeLa Cells | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | S Phase | es_ES |
dc.subject.mesh | Transcription Factors | es_ES |
dc.title | Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 18579778 | es_ES |
dc.format.volume | 105 | es_ES |
dc.format.number | 26 | es_ES |
dc.format.page | 8956 | es_ES |
dc.identifier.doi | 10.1073/pnas.0803978105 | es_ES |
dc.contributor.funder | Fundación Caja Madrid | es_ES |
dc.contributor.funder | Ministerio de Ciencia (España) | es_ES |
dc.contributor.funder | Marie Curie | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1091-6490 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1073/pnas.0803978105. | es_ES |
dc.identifier.journal | Proceedings of the National Academy of Sciences of the United States of America | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Replicación de ADN | es_ES |
dc.rights.accessRights | open access | es_ES |