Effect of sequence context on the formation and repair of DNA adducts.

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Effect of sequence context on the formation and repair of DNA adducts.

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Guza, Rebecca Clare

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2009-08

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Abstract

Tobacco smoke contains over sixty known carcinogens and following exposure can lead to the formation of DNA adducts. Persistence of nucleobase adducts in DNA can lead to polymerase errors, mutations in critical gene, and tumor initiation. However, a specialized repair protein, O6-alkylguanine DNA alkyltransferase (AGT), recognizes and repairs the O6-alkyl-dG adducts. Major targets for mutations in smoking induced lung cancer are the K-ras proto-oncogene and the p53 tumor suppressor gene. Mutational hotspots in the p53 gene are concentrated at endogenously methylated CG dinucleotides in exons 5-8. These sites contain 5-methylcytosine (MeC), which is known to alter DNA structure and stability. We hypothesized that MeC may contribute to carcinogenesis by influencing the formation and repair of tobacco carcinogen-DNA adducts within critical genes. In our studies, mass spectrometry based methodologies were used to analyze the kinetics of AGT repair of O6-Me-dG and to investigate the mechanisms of MeC mediated effects on DNA adduct formation at MeC:G base pairs. We found that the rate of AGT-mediated repair of O6-Me-dG lesions is influenced by local sequence context and in particular, can be mediated by endogenous cytosine methylation. MeC can also mediate the formation of N2-BPDE-dG adducts by influencing the formation of pre-covalent and intercalative complexes between DNA and BPDE. This work contributes to our understanding of the role of sequence context and endogenous cytosine methylation in the formation and repair of DNA adducts induced by tobacco carcinogens.

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Biochemistry, Molecular Bio, and Biophysics

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University of Minnesota Ph.D. dissertation. August 2009. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Dr. Natalia Tretyakova. 1 computer file (PDF); xvi, 2002 pages.

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Guza, Rebecca Clare. (2009). Effect of sequence context on the formation and repair of DNA adducts.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/54180.

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