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.
Highlights
Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation
To inflict different types of DNA damage we used 12 genotoxic agents encompassing UV-B, X- and γ-radiation; the alkylating agents ethyl methanesulfonate (EMS), dimethyl sulfate (DMS) and methyl methanesulfonate (MMS); aristolochic acid (AA) and aflatoxin B1, which form bulky DNA adducts; hydroxyurea as a replication fork stalling agent; and cisplatin, mechlorethamine and mitomycin C known to form DNA intra- and inter-strand crosslinks
The systematic nature of the screen with multiple known doses of different genotoxins applied across a broad range of genetic backgrounds enabled us to precisely characterise how mutation patterns of genotoxic treatments change under concomitant DNA repair deficiency
Summary
Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. The analysis of thousands of cancer genomes and exomes led to the discovery of more than 50 mutational signatures of base substitutions[1,2] Some of these signatures, deduced by computational pattern recognition, have evident associations with exposure to known mutagens such as UV light, tobacco smoke, the food contaminants aristolochic acid (AA) and aflatoxins[3,4,5], or with DNA repair deficiency syndromes and compromised DNA replication[1,6,7]. Combining genotoxin exposure and DNA repair deficiency in many cases led to altered mutagenesis, signified by either higher or lower mutation rates or altered mutation spectra compared to DNA repair deficiency or wild-type genotoxin exposure alone These interactions highlight how different DNA lesions induced by the same genotoxin are processed by a number of DNA repair pathways, often specific for a particular type of DNA damage, changing mutation spectra usually in subtle but sometimes dramatic ways. Our data imply that mutational signatures derived from cancer genomes can be variable, and may not have a one-to-one relationship to distinct mutagenic processes
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