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Whole genome mutational profiling of the chemotherapeutic agent mitomycin C

University of British Columbia

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 I have characterized the mutational spectrum of a commonly used DNA interstrand crosslinking agent mitomycin C (MMC). Using a combination of genetic mapping, whole-genome sequencing, and bioinformatics tools, I have identified and confirmed several genomic lesions linked to MMC-induced DNA damage. These results indicate that MMC predominantly causes deletions, with a 5'-CpG-3' sequence context prevalent in the deleted regions of DNA. Furthermore, I identified microhomology flanking the deletion junctions, indicative of DNA repair via non-homologous end joining. Based on these results, I 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 I have described provides insight into potential sequence specificity of MMC with DNA.

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2014-06-17

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/47013

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/