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The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions

 

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dc.creator Orta Vázquez, Manuel Luis es
dc.creator Höglund, Andreas es
dc.creator Calderón Montaño, José Manuel es
dc.creator Domínguez García, Inmaculada es
dc.creator Burgos Morón, Estefanía es
dc.creator Visnes, Torkild es
dc.creator Pastor Carrillo, Nuria María es
dc.creator Ström, Cecilia es
dc.creator López Lázaro, Miguel es
dc.creator Helleday, Thomas es
dc.date.accessioned 2016-05-17T07:56:04Z
dc.date.available 2016-05-17T07:56:04Z
dc.date.issued 2014
dc.identifier.issn 0305-1048 es
dc.identifier.uri http://hdl.handle.net/11441/41298
dc.description.abstract Decitabine (5-aza-21-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) rec- ognizes 5-azadC-induced lesions in DNA and medi- ates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci af- ter 5-azadC treatment, suggesting a novel and spe- cific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defec- tive cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relo- cation to DNA damage sites, disrupts XRCC1–DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5- azadC to improve treatment of MDS and AML. es
dc.format application/pdf es
dc.language.iso eng es
dc.publisher Oxford University Press es
dc.relation.ispartof Nucleic Acids Research, 42, (14), 9108-9120 es
dc.rights Attribution-NonCommercial-NoDerivatives 4.0 Internacional *
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/ *
dc.subject 5 aza 2' deoxycytidine es
dc.subject DNA es
dc.subject DNA methyltransferase 1 es
dc.subject Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase es
dc.subject Olaparib es
dc.subject XRCC1 protein es
dc.title The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions 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.relation.publisherversion 10.1093/nar/gku638 es
dc.identifier.doi http://dx.doi.org/10.1093/nar/gku638 es
idus.format.extent 13 p. es
dc.identifier.idus https://idus.us.es/xmlui/handle/11441/41298
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