Journal
G3-GENES GENOMES GENETICS
Volume 6, Issue 1, Pages 133-140Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.115.021915
Keywords
whole genome sequencing; C. elegans; model organism; mutation spectrum; mitomycin C
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Funding
- National Science and Engineering Research Council (NSERC)
- Canadian Institutes of Health Research (Canada) (CIHR)
- CIHR Fanconi Anemia Postdoctoral Fellowship
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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.
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