John Pierce Wise, Naga D. Karri and Hong Xie
Accepted Abstracts: J Cancer Sci Ther
Naturally occurring repetitive DNA sequences can adopt alternatively structured DNA (i.e., non-B DNA), and often map near chromosomal breakpoint ?hotspots?, implicating non-B DNA in translocation-related cancer etiology. We have found that two types of non-B DNA structures, H-DNA and Z-DNA, 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 mutations in mammalian cells, largely in the form of deletions resulting from DNA double-strand breaks. Characterization of the mutants revealed microhomologies at the breakpoints, consistent with a microhomology-mediated end-joining repair of the double-strand breaks. We have constructed transgenic mutation-reporter mice containing these human H-DNA-forming and Z-DNA-forming sequences, to determine their effects on genomic instability in a chromosomal context in animals. We found that both H-DNA- and Z-DNA-forming sequences stimulated genetic instability in mice, suggesting that these non-B DNA-forming sequences represent endogenous sources of genetic instability. These results demonstrate that naturally occurring DNA sequences are mutagenic in mammalian cells and may contribute to disease etiology and evolution. Our current studies are designed to determine the roles of mammalian helicases, polymerases, and DNA repair enzymes in an effort to elucidate the mechanism(s) involved in non-B DNA-induced genetic instability.
Karen M. Vasquez?s research efforts are focused within an overall theme of genome instability, DNA damage, and mechanisms of repair. She has worked in these fields for more than 20 years, and has published more than 75 peer-reviewed papers in these areas. She serves on the editorial boards for Molecular Carcinogenesis, Mutation Research, DNA Repair, Environmental and Molecular Mutagenesis,New Journal of Science, andtheJournal of Biological Chemistry . She is a member of the Board of Scientific Counselors for the NIEHS, and has served on numerous review committees for NIH and other funding organizations both nationally and internationally