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 languageEnglish
Article number2169
Pages (from-to)1-15
Number of pages15
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 1 May 2020

Keywords

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

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    Volkova, N. V., Meier, B., González-Huici, V., Bertolini, S., Gonzalez, S., Vöhringer, H., Abascal, F., Martincorena, I., Campbell, P. J., Gartner, A., & Gerstung, M. (2020). Mutational signatures are jointly shaped by DNA damage and repair. Nature Communications, 11, 1-15. [2169]. https://doi.org/10.1038/s41467-020-15912-7