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Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes

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dc.contributor.author Supek, Fran
dc.contributor.author Lehner, Ben, 1978-
dc.date.accessioned 2018-08-21T06:18:20Z
dc.date.available 2018-08-21T06:18:20Z
dc.date.issued 2017
dc.identifier.citation Supek F, Lehner B. Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes. Cell. 2017 Jul 27 ;170(3): 534-547.e23. DOI: 10.1016/j.cell.2017.07.003
dc.identifier.issn 0092-8674
dc.identifier.uri http://hdl.handle.net/10230/35343
dc.description.abstract Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.
dc.description.sponsorship This work was supported by grants from the ERC (616434), MINECO (BFU2011-26206 and SEV-2012-0208), AXA Research Fund (AXA Chair in Risk Prediction in Age-related Diseases), Bettencourt Schueller Foundation, AGAUR (2014 SGR 831), FP7 (projects 4DCellFate 277899, MAESTRA ICT-2013-612944, and InnoMol FP7-REGPOT-2012-2013-1-316289), the EMBL-CRG Systems Biology Program, and the CERCA program
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.cell.2017.07.003 that appeared in the journal Cell. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-license
dc.subject.other ADN -- Reparació
dc.subject.other Tumors -- Genètica
dc.title Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.cell.2017.07.003
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/612944
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/316289
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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