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dc.contributor.authorÁlvarez-Quilón, Alejandro
dc.contributor.authorTerrón-Bautista, José
dc.contributor.authorDelgado-Sainz, Irene
dc.contributor.authorSerrano-Benítez, Almudena
dc.contributor.authorRomero-Granados, Rocío
dc.contributor.authorMartínez-García, Pedro Manuel
dc.contributor.authorJimeno-González, Silvia
dc.contributor.authorBernal-Lozano, Cristina
dc.contributor.authorQuintero, Cristina
dc.contributor.authorGarcía-Quintanilla, Lourdes
dc.contributor.authorCortes-Ledesma, Felipe 
dc.date.accessioned2020-03-20T17:19:12Z
dc.date.available2020-03-20T17:19:12Z
dc.date.issued2020-02-14
dc.identifier.citationNat Commun. 2020;14;11(1):910.es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9295
dc.description.abstractThe 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.sponsorshipThis 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.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleEndogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiencyes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID32060399es_ES
dc.format.volume11es_ES
dc.format.number1es_ES
dc.format.page910es_ES
dc.identifier.doi10.1038/s41467-020-14638-wes_ES
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderRegional Government of Andalusia (España) 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.contributor.funderAsociación Española Familia Ataxia Telangiectasia 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-1723es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-020-14638-w.es_ES
dc.identifier.journalNature communicationses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigaciónes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2010-21017es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2013-47343-Pes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2017-89619-Res_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/CVI-7948es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/EC/H2020/647359es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/BES-66BES-2011-047351es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/FPU15/03656es_ES
dc.rights.accessRightsopen accesses_ES


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