Mutational signatures are jointly shaped by DNA damage and repair
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Authors
Meier, Bettina
González-Huici, Víctor
Bertolini, Simone
Vöhringer, Harald
Martincorena, Iñigo
Publication Date
2020-05-01Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
11
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Volkova, N. V., Meier, B., González-Huici, V., Bertolini, S., Gonzalez, S., Vöhringer, H., Abascal, F., et al. (2020). Mutational signatures are jointly shaped by DNA damage and repair. Nature Communications, 11 (1) https://doi.org/10.1038/s41467-020-15912-7
Description
Funder: Biotechnology and Biological Sciences Research Council East of Scotland Bioscience Doctoral Training Partnership Ph.D. studentship
Funder: Korean Institute for Basic Science, IBS-R022-A1-2019
Abstract
Abstract: Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.
Keywords
Article, /631/67/69, /631/114/2397, /631/337/1427, /631/337/1427/1430, /631/337/1427/2354, /45/70, /45/23, /64/11, article
Sponsorship
Worldwide Cancer Research (18-0644)
Cancer Research UK (CRUK) (C11852/A14695)
Identifiers
s41467-020-15912-7, 15912
External DOI: https://doi.org/10.1038/s41467-020-15912-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315441
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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