title: Genome-Wide Mutational Signature of the Chemotherapeutic Agent Mitomycin C in Caenorhabditis elegans.
abstract: Cancer therapy largely depends on chemotherapeutic agents that generate DNA lesions. However, our understanding of the nature of the resulting lesions as well as the mutational profiles of these chemotherapeutic agents is limited. Among these lesions, DNA interstrand crosslinks are among the more toxic types of DNA damage. Here, we have characterized the mutational spectrum of the commonly used DNA interstrand crosslinking agent mitomycin C (MMC). Using a combination of genetic mapping, whole genome sequencing, and genomic analysis, we have identified and confirmed several genomic lesions linked to MMC-induced DNA damage in Caenorhabditis elegans. Our data indicate that MMC predominantly causes deletions, with a 5'-CpG-3' sequence context prevalent in the deleted regions of DNA. Furthermore, we identified microhomology flanking the deletion junctions, indicative of DNA repair via nonhomologous end joining. Based on these results, we propose a general repair mechanism that is likely to be involved in the biological response to this highly toxic agent. In conclusion, the systematic study we have described provides insight into potential sequence specificity of MMC with DNA.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, V6T 1Z3, Canada Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, V5Z 1L3, Canada atam@bccrc.ca.
authors.forename: Annie S
authors.initials: AS
authors.lastname: Tam
authors.affiliation: WuHan Frasergen Bioinformatics Co. Ltd., Wuhan, Hubei Province, 430075, China.
authors.forename: Jeffrey S C
authors.initials: JS
authors.lastname: Chu
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, V6T 1Z3, Canada.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Rose
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics*; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods; D004249:DNA Damage / Q000187:drug effects; D005804:Genes, Lethal; D016678:Genome; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D016685:Mitomycin / Q000633:toxicity*; D016254:Mutagenesis, Insertional; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects*; D059645:Mutation Rate; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D016685:Mitomycin
keywords: C. elegans; mitomycin C; model organism; mutation spectrum; whole genome sequencing