Mutational signatures are jointly shaped by DNA damage and repair

Nadezda V. Volkova; Bettina Meier; Víctor González-Huici; Simone Bertolini; Santiago Gonzalez; Harald Vöhringer; Federico Abascal; Iñigo Martincorena; Peter J. Campbell; Anton Gartner; Moritz Gerstung

doi:10.1038/s41467-020-15912-7

Mutational signatures are jointly shaped by DNA damage and repair

Nadezda V. Volkova, Bettina Meier, Víctor González-Huici, Simone Bertolini, Santiago Gonzalez, Harald Vöhringer, Federico Abascal, Iñigo Martincorena, Peter J. Campbell, Anton Gartner (Lead / Corresponding author), Moritz Gerstung (Lead / Corresponding author)

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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.

Original language	English
Article number	2169
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-15912-7
Publication status	Published - 1 May 2020

Keywords

Cancer genomics
Computational models
DNA damage and repair
Nucleotide excision repair
Translesion synthesis

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-15912-7Licence: CC BY

Final Published VersionFinal published version, 3.4 MBLicence: CC BY

Cite this

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title = "Mutational signatures are jointly shaped by DNA damage and repair",

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.",

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author = "Volkova, {Nadezda V.} and Bettina Meier and V{\'i}ctor Gonz{\'a}lez-Huici and Simone Bertolini and Santiago Gonzalez and Harald V{\"o}hringer and Federico Abascal and I{\~n}igo Martincorena and Campbell, {Peter J.} and Anton Gartner and Moritz Gerstung",

note = "Funding Information: This work was supported by the Wellcome Trust COMSIG consortium grant RG70175, a Wellcome Trust Senior Research award (090944/Z/09/Z), a Worldwide Cancer Research grant (18-0644), and by the Korean Institute for Basic Science (IBS-R022-A1-2019) to AG. We thank the Mitani Lab funded by the National Bio-Resource Project of the MEXT, Japan, and the Caenorhabditis Genetics Center funded by the NIH Office of Research Infrastructure Programs (P40 OD010440) for providing strains. Nadezda Volkova is a member of Lucy Cavendish College, University of Cambridge. We thank Nuria Lopez-Bigas for critical comments on the paper. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Volkova, Nadezda V.

AU - Meier, Bettina

AU - González-Huici, Víctor

AU - Bertolini, Simone

AU - Gonzalez, Santiago

AU - Vöhringer, Harald

AU - Abascal, Federico

AU - Martincorena, Iñigo

AU - Campbell, Peter J.

AU - Gartner, Anton

AU - Gerstung, Moritz

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N2 - 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.

AB - 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.

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Mutational signatures are jointly shaped by DNA damage and repair

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Processing of Branched DNA Molecules During Cytokinesis, Uncovering New Mechanisms of Genome Maintenance

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Mutational signatures are jointly shaped by DNA damage and repair

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Processing of Branched DNA Molecules During Cytokinesis, Uncovering New Mechanisms of Genome Maintenance

Cite this