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dc.contributor.authorReijns, MAM
dc.contributor.authorParry, DA
dc.contributor.authorWilliams, TC
dc.contributor.authorNadeu, F
dc.contributor.authorHindshaw, RL
dc.contributor.authorRios Szwed, DO
dc.contributor.authorNicholson, MD
dc.contributor.authorCarroll, P
dc.contributor.authorBoyle, S
dc.contributor.authorRoyo, R
dc.contributor.authorCornish, AJ
dc.contributor.authorXiang, H
dc.contributor.authorRidout, K
dc.contributor.authorGenomics England Research Consortium
dc.contributor.authorColorectal Cancer Domain UK 100, 000 Genomes Project
dc.contributor.authorSchuh, A
dc.contributor.authorAden, K
dc.contributor.authorPalles, C
dc.contributor.authorCampo, E
dc.contributor.authorStankovic, T
dc.contributor.authorTaylor, MS
dc.contributor.authorJackson, AP
dc.date.accessioned2022-02-23T14:23:38Z
dc.date.available2022-02-23T14:23:38Z
dc.date.issued2022-02-09
dc.identifier.citationNature, 2022en_US
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5037
dc.identifier.eissn1476-4687en_US
dc.identifier.eissn1476-4687
dc.identifier.doi10.1038/s41586-022-04403-yen_US
dc.identifier.doi10.1038/s41586-022-04403-y
dc.description.abstractThe mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair<sup>1</sup>. In microorganisms, transcription has been demonstrated to be mutagenic<sup>2,3</sup>; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes<sup>4</sup>. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology<sup>5</sup> characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress<sup>6</sup>, their activity may also be an important source of mutations in the human genome.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectGenomics England Research Consortiumen_US
dc.subjectColorectal Cancer Domain UK 100,000 Genomes Projecten_US
dc.titleSignatures of TOP1 transcription-associated mutagenesis in cancer and germline.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-01-04
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1038/s41586-022-04403-yen_US
rioxxterms.licenseref.startdate2022-02-09
dc.relation.isPartOfNatureen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Genomics
dc.contributor.icrauthorCornish, Alexanderen_US
dc.contributor.icrauthorHoulston, Richarden_US


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