Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
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. & Vasquez K.M. (2004). Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 101:13448-13453.

    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.

Guliang Wang
Laura A. Christensen
Karen M. Vasquez

Division of Pharmacology and Toxicology
The University of Texas at Austin
1400 Barbara Jordan Blvd.
Dell Pediatric Research Institute
Austin, TX 78723

Ph: (512) 495-3040
FAX: (512) 495-4945