Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
DNA Structure-induced Genetic Instability in Mammals
Naturally occurring repetitive DNA sequences can adopt alternative (i.e. non-B) DNA secondary structures, and often co-localize with chromosomal breakpoint “hotspots”, implicating non-B DNA in translocation-related cancer etiology. We have found that sequences capable of adopting H-DNA and Z-DNA structures are intrinsically mutagenic in mammals. For example, an endogenous H-DNA-forming sequence from the human c-MYC promoter and a model Z-DNA-forming CpG repeat induced genetic instability in mammalian cells, largely in the form of deletions resulting from DNA double-strand breaks (Wang & Vasquez, 2004; Wang et al., 2006). Characterization of the mutants revealed microhomologies at the breakpoints, consistent with a microhomology-mediated end-joining repair of the double-strand breaks (Kha et al., 2010). We have constructed transgenic mutation-reporter mice containing these human H-DNA and Z-DNA-forming sequences to determine their effects on genomic instability in a chromosomal context in a living organism (Wang et al., 2008). Initial results suggest that both H-DNA- and Z-DNA-forming sequences induced genetic instability in mice, suggesting that these non-B DNA structures represent endogenous sources of genetic instability and may contribute to disease etiology and evolution. Our current studies are designed to determine the mechanisms of DNA structure-induced genetic instability in mammals; the roles of helicases, polymerases, and repair enzymes in H-DNA and Z-DNA-induced genetic instability will be discussed.
This work was supported by grants from the National Institutes of Health (CA097175 and CA093729) to K.M.V.
Wang G., Christensen L.A., Vasquez K.M. (2006). Z-DNA-forming sequences induce large-scale deletions in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 103:2677-2682.
Kha D.T., Wang G., Natrajan N., Harrison L., Vasquez K.M. (2010). Pathways for double-strand break repair in genetically unstable Z-DNA-forming sequences. Journal of Molecular Biology 398:471-480.
Wang G., Carbajal S., Vijg J., DiGiovanni J., Vasquez K.M. (2008). DNA structure-induced genomic instability in vivo. Journal of the National Cancer Institute 100(24):1815-1817.
Division of Pharmacology and Toxicology