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dc.contributor.authorAlvarez-Prado, Angel Francisco 
dc.contributor.authorPerez-Duran, Pablo 
dc.contributor.authorPerez-Garcia, Arantxa 
dc.contributor.authorBenguria, Alberto 
dc.contributor.authorTorroja, Carlos 
dc.contributor.authorde Yebenes, Virginia G 
dc.contributor.authorRamiro, Almudena R 
dc.date.accessioned2018-10-26T07:59:28Z
dc.date.available2018-10-26T07:59:28Z
dc.date.issued2018
dc.identifierISI:000440812100006
dc.identifier.citationJ Exp Med. 2018; 215(3):761-771
dc.identifier.issn0022-1007
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6545
dc.description.abstractActivation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth > 1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.
dc.description.sponsorshipA. Perez-Garcia was a fellow of the research training program funded by the Ministerio de Educacion, Cultura y Deporte (grant FPU-AP2009-1732); A.F. Alvarez-Prado and A.R. Ramiro are supported by Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). This work was funded with the following grants to A.R. Ramiro from Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016, Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigacion: Proyectos I+D+i 2016, Ministerio de Economia, Industria y Competitividad (MEIC; grants SAF2013-42767-R and SAF2016-75511-R). This work is cofunded by Fondo Europeo de Desarrollo Regional and the European Research Council Starting Grant program (grant BCL YM-207844). The CNIC is supported by the MEIC and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505).
dc.language.isoeng
dc.publisherRockefeller University Press 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectINDUCED CYTIDINE DEAMINASE
dc.subjectB-CELL LYMPHOMAS
dc.subjectCLASS SWITCH RECOMBINATION
dc.subjectSEQUENCING REVEALS
dc.subjectGENOMIC INSTABILITY
dc.subjectSUPER-ENHANCERS
dc.subjectDEFICIENT MICE
dc.subjectDNA BREAKS
dc.subjectIG GENES
dc.subjectC-MYC
dc.titleA broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID29374026
dc.format.volume215
dc.format.page761-771
dc.identifier.doi10.1084/jem.20171738
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España) 
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderFundación ProCNIC 
dc.description.peerreviewed
dc.identifier.e-issn1540-9538
dc.relation.publisherversionhttps://doi.org/10.1084/jem.20171738
dc.identifier.journalJournal of Experimental Medicine
dc.repisalud.orgCNICCNIC::Grupos de investigación::Biología de linfocitos B
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformática
dc.repisalud.institucionCNIC
dc.rights.accessRightsopen accesses_ES


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