Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 (Print) 1538-0254 (Online) Journal homepage: http://www.tandfonline.com/loi/tbsd20
118 DNA structure-induced genetic instability in mammals Guliang Wang , Laura A. Christensen & Karen M. Vasquez To cite this article: Guliang Wang , Laura A. Christensen & Karen M. Vasquez (2013) 118 DNA structure-induced genetic instability in mammals, Journal of Biomolecular Structure and Dynamics, 31:sup1, 75-75, DOI: 10.1080/07391102.2013.786360 To link to this article: http://dx.doi.org/10.1080/07391102.2013.786360
Published online: 29 May 2013.
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Date: 14 January 2017, At: 08:55
Book of Abstracts. Albany 2013: The 18th Conversation replicated DNA, suggested a replicated-independent pathway of Z-DNA-induced genetic instability (Wang, Christensen, & Vasquez, 2004). Several DNA repair proteins were found to be involved in Z-DNA induced mutagenesis, but in different ways: adding XPA protein back in, otherwise, deficient XP12RO cells increased Z-DNA-induced mutation frequency by 50%, while expressing MSH2 protein in Hec59 cells reduced Z-DNA-induced mutation frequency by 25%. Interestingly, cytosine methylation in CpG repeats induced higher frequencies of deletions and rearrangements with a broader mutant size distribution than that found with unmethylated CpG repeats. We discovered that unusual structural features of the methylated CpG sequences precluded local nucleosome assembly leading to genetic instability. Thus, non-B DNA-induced mutation appears to be a very complex process where DNA replication, repair and epigenetic modification are all involved. This work was supported by an NIH/NCI grant to K.M. V. (CA093729).
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induced genetic instability in mammalian cells, largely in the form of deletions resulting from DNA doublestrand 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 doublestrand 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 ZDNA-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.
References 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, 1815–1817. Wang, G., Christensen, L. A., & Vasquez, K. M. (2006). ZDNA-forming sequences generate large-scale deletions in mammalian cells. Proceedings of the National academy of Sciences of the United States of America, 103, 2677–2682. Zhao, J., Bacolla, A., Wang, G., & Vasquez, K. M. (2010). NonB DNA structure-induced genetic instability and evolution. Cellular and Molecular Life Sciences, 67, 43–62.
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DNA structure-induced genetic instability in mammals
Guliang Wang, Laura A. Christensen and 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 *Email:
[email protected], Phone: (512) 4953040, Fax: (512) 495-4945
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
References 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, 1815– 1817. Wang, G., Christensen, L. A., & Vasquez, K. M. (2006). Z-DNA-forming sequences induce large-scale deletions in mammalian cells. Proceedings of the National Academy of Sciences of the USA, 103, 2677–2682. Wang, G., & Vasquez, K. M. (2004). Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells. Proceedings of the National Academy of Sciences of the USA, 101, 13448–13453.
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Fork stalling at AT-rich sequences and failure of origin activation lead to chromosomal instability at fragile sites
Efrat Ozeri-Galai, Michal Irony-Tur Sinai and Batsheva Kerem* Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel 91904 *Email:
[email protected], Phone: (972)-2-6585689, Fax: (972) 2-2 6584810
