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5-Aza-2'-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair

 

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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
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 10.1093/nar/gkt270 es
dc.identifier.doi http://dx.doi.org/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
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