dc.creator | Orta Vázquez, Manuel Luis | es |
dc.creator | Calderón Montaño, José Manuel | es |
dc.creator | Domínguez García, Inmaculada | es |
dc.creator | Pastor Carrillo, Nuria María | es |
dc.creator | Burgos Morón, Estefanía | es |
dc.creator | López Lázaro, Miguel | es |
dc.creator | Cortés, Felipe | es |
dc.creator | Mateos Cordero, Santiago | es |
dc.creator | Helleday, Thomas | es |
dc.date.accessioned | 2017-04-27T10:16:25Z | |
dc.date.available | 2017-04-27T10:16:25Z | |
dc.date.issued | 2013 | |
dc.identifier.citation | Orta Vázquez, M.L., Calderón Montaño, J.M., Domínguez García, I., Pastor Carrillo, N.M., Burgos Morón, E., López Lázaro, M.,...,Helleday, T. (2013). 5-Aza-20-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair. Nucleic Acids Research, 41 (11), 5827-5836. | |
dc.identifier.issn | 0305-1048 | es |
dc.identifier.uri | http://hdl.handle.net/11441/58754 | |
dc.description.abstract | 5-Aza-2'-deoxycytidine (5-azadC) is a DNA methyltransferase (DNMT) inhibitor increasingly used in treatments of hematological diseases and works by being incorporated into DNA and trapping DNMT. It is unclear what DNA lesions are caused by 5-azadC and if such are substrates for DNA repair. Here, we identify that 5-azadC induces DNA damage as measured by γ-H2AX and 53BP1 foci. Furthermore, 5-azadC induces radial chromosomes and chromatid breaks that depend on active replication, which altogether suggest that trapped DNMT collapses oncoming replication forks into double-strand breaks. We demonstrate that RAD51-mediated homologous recombination (HR) is activated to repair 5-azadC collapsed replication forks. Fanconi anemia (FA) is a rare autosomal recessive disorder, and deaths are often associated with leukemia. Here, we show that FANCG-deficient cells fail to trigger HR-mediated repair of 5-azadC-induced lesions, leading to accumulation of chromatid breaks and inter-chromosomal radial fusions as well as hypersensitivity to the cytotoxic effects of 5-azadC. These data demonstrate that the FA pathway is important to protect from 5-azadC-induced toxicity. Altogether, our data demonstrate that cytotoxicity of the epigenetic drug 5-azadC can, at least in part, be explained by collapsed replication forks requiring FA-mediated HR for repair. | es |
dc.description.sponsorship | Ministerio de Educación y Ciencia BFU2007- 61301 | es |
dc.description.sponsorship | Junta de Andalucía BIO-120 | es |
dc.format | application/pdf | es |
dc.language.iso | eng | es |
dc.publisher | Oxford University Press | es |
dc.relation.ispartof | Nucleic Acids Research, 41 (11), 5827-5836. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.title | 5-Aza-2'-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Biología Celular | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Farmacología | es |
dc.relation.projectID | BFU2007- 61301 | es |
dc.relation.projectID | BIO-120 | es |
dc.relation.publisherversion | http://dx.doi.org/10.1093/nar/gkt270 | es |
dc.identifier.doi | 10.1093/nar/gkt270 | es |
idus.format.extent | 10 p. | es |
dc.journaltitle | Nucleic Acids Research | es |
dc.publication.volumen | 41 | es |
dc.publication.issue | 11 | es |
dc.publication.initialPage | 5827 | es |
dc.publication.endPage | 5836 | es |
dc.contributor.funder | Ministerio de Educación y Ciencia (MEC). España | |
dc.contributor.funder | Junta de Andalucía | |