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dc.contributor.authorDíaz-Talavera, Alberto
dc.contributor.authorCalvo, Patricia A
dc.contributor.authorGonzalez-Acosta, Daniel 
dc.contributor.authorDíaz, Marcos
dc.contributor.authorSastre-Moreno, Guillermo
dc.contributor.authorBlanco-Franco, Luis
dc.contributor.authorGuerra, Susana
dc.contributor.authorMartínez-Jiménez, Maria I
dc.contributor.authorMendez, Juan 
dc.contributor.authorBlanco, Luis
dc.date.accessioned2019-05-24T08:41:08Z
dc.date.available2019-05-24T08:41:08Z
dc.date.issued2019-02-04
dc.identifier.citationSci Rep. 2019 ;9(1):112.es_ES
dc.identifier.issn2045-2322es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7673
dc.description.abstractPrimPol is a human primase/polymerase specialized in re-starting stalled forks by repriming beyond lesions such as pyrimidine dimers, and replication-perturbing structures including G-quadruplexes and R-loops. Unlike most conventional primases, PrimPol proficiently discriminates against ribonucleotides (NTPs), being able to start synthesis using deoxynucleotides (dNTPs), yet the structural basis and physiological implications for this discrimination are not understood. In silico analyses based on the three-dimensional structure of human PrimPol and related enzymes enabled us to predict a single residue, Tyr100, as the main effector of sugar discrimination in human PrimPol and a change of Tyr100 to histidine to boost the efficiency of NTP incorporation. We show here that the Y100H mutation profoundly stimulates NTP incorporation by human PrimPol, with an efficiency similar to that for dNTP incorporation during both primase and polymerase reactions in vitro. As expected from the higher cellular concentration of NTPs relative to dNTPs, Y100H expression in mouse embryonic fibroblasts and U2OS osteosarcoma cells caused enhanced resistance to hydroxyurea, which decreases the dNTP pool levels in S-phase. Remarkably, the Y100H PrimPol mutation has been identified in cancer, suggesting that this mutation could be selected to promote survival at early stages of tumorigenesis, which is characterized by depleted dNTP pools.es_ES
dc.description.sponsorshipWe are thankful to Professor Ian J. Holt (BioDonostia, San Sebastian, Spain), for critical reading of the manuscript. We thank Sara Rodriguez-Acebes (CNIO) for advice regarding the assays with stretched DNA fibers. This study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO; BFU2012–3769, BFU2014– 51672-REDC and BFU2015–65880-P (co-funded with European Union FEDER funds) to L.B.; BFU2013– 49153-P and BFU2016–80402-R (co-funded with European Union FEDER funds) to J.M.). A.D.T., P.A.C. and D.G.A. are recipients of MINECO FPI-predoctoral fellowships. M.D. was the recipient of a FPI-predoctoral fellowship from Programa de Excelencia “Severo Ochoa” (CNIO-MINECO). G.S.M was the recipient of a JAE Predoctoral Fellowship from the Spanish Research Council (CSIC). Funding for open access charge: Spanish MINECO [BFU2015–65880-P]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.subjectDNA-POLYMERASEes_ES
dc.subjectENZYMEes_ES
dc.subjectRIBONUCLEOTIDE INCORPORATIONes_ES
dc.subjectKINETIC-ANALYSISes_ES
dc.subjectREPLICATIONes_ES
dc.subjectPRIMASEes_ES
dc.subjectGENOMEes_ES
dc.subjectRNAes_ES
dc.subjectNUCLEOTIDEes_ES
dc.subjectPROTEINes_ES
dc.titleA cancer-associated point mutation disables the steric gate of human PrimPoles_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID30718533es_ES
dc.format.volume9es_ES
dc.format.number1es_ES
dc.format.page1121es_ES
dc.identifier.doi10.1038/s41598-018-37439-0es_ES
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderFundación General (CSIC) 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2045-2322es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41598-018-37439-0.es_ES
dc.identifier.journalScientific reportses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Replicación de ADNes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2012-3769es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2014-51672-REDCes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2013-49153-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2016-80402-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2015-65880-Pes_ES
dc.rights.accessRightsopen accesses_ES


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