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dc.contributor.author | Álvarez-Quilón, Alejandro | |
dc.contributor.author | Terrón-Bautista, José | |
dc.contributor.author | Delgado-Sainz, Irene | |
dc.contributor.author | Serrano-Benítez, Almudena | |
dc.contributor.author | Romero-Granados, Rocío | |
dc.contributor.author | Martínez-García, Pedro Manuel | |
dc.contributor.author | Jimeno-González, Silvia | |
dc.contributor.author | Bernal-Lozano, Cristina | |
dc.contributor.author | Quintero, Cristina | |
dc.contributor.author | García-Quintanilla, Lourdes | |
dc.contributor.author | Cortes-Ledesma, Felipe | |
dc.date.accessioned | 2020-03-20T17:19:12Z | |
dc.date.available | 2020-03-20T17:19:12Z | |
dc.date.issued | 2020-02-14 | |
dc.identifier.citation | Nat Commun. 2020;14;11(1):910. | es_ES |
dc.identifier.issn | 2041-1723 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/9295 | |
dc.description.abstract | The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor whose loss is the cause of the neurodegenerative and cancer-prone syndrome Ataxia-Telangiectasia (A-T). A-T patients and Atm-/- mouse models are particularly predisposed to develop lymphoid cancers derived from deficient repair of RAG-induced DSBs during V(D)J recombination. Here, we unexpectedly find that specifically disturbing the repair of DSBs produced by DNA topoisomerase II (TOP2) by genetically removing the highly specialised repair enzyme TDP2 increases the incidence of thymic tumours in Atm-/- mice. Furthermore, we find that TOP2 strongly colocalizes with RAG, both genome-wide and at V(D)J recombination sites, resulting in an increased endogenous chromosomal fragility of these regions. Thus, our findings demonstrate a strong causal relationship between endogenous TOP2-induced DSBs and cancer development, confirming these lesions as major drivers of ATM-deficient lymphoid malignancies, and potentially other conditions and cancer types. | es_ES |
dc.description.sponsorship | This work has been funded with grants from the Spanish and Andalusian Government(SAF2010-21017, SAF2013-47343-P, SAF2014-55532-R, SAF2017-89619-R, CVI-7948,European Regional Development Fund), and the European Research Council (ERC-CoG-2014-647359); and with individual fellowships for AAQ (Formación Personal Investiga-dor, BES-2011-047351, Ministerio de Ciencia e Innovación), JTB (Formación ProfesoradoUniversitario, FPU15/03656, Ministerio de Educación, Cultura y Deporte) and ASB (BecaPredoctoral AEFAT, Asociación Española Familia Ataxia Telangiectasia). CABIMER issupported by the Andalusian Government. Computational analyses were run on the HighPerfomance Computing cluster provided by the Centro Informático Científico de Andalucía (CICA). We thank the Genomics facility at CABIMER for CGH and NGSexperiments, O. Fernández-Capetillo for reagents and A. Aguilera for comments. | 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.title | Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 32060399 | es_ES |
dc.format.volume | 11 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 910 | es_ES |
dc.identifier.doi | 10.1038/s41467-020-14638-w | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.contributor.funder | Regional Government of Andalusia (España) | |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | |
dc.contributor.funder | Asociación Española Familia Ataxia Telangiectasia | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2041-1723 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-020-14638-w. | es_ES |
dc.identifier.journal | Nature communications | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2010-21017 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2013-47343-P | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2017-89619-R | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/CVI-7948 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/EC/H2020/647359 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/BES-66BES-2011-047351 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/FPU15/03656 | es_ES |
dc.rights.accessRights | open access | es_ES |