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oai:opus.uleth.ca:10133/53372019-05-27T15:24:43Zcom_10133_3346com_10133_1com_10133_296col_10133_3347col_10133_298

Wetmore, Stacey D. Wilson, Katie A. University of Lethbridge. Faculty of Arts and Science 2019-04-24T17:18:01Z 2019-04-24T17:18:01Z 2018 https://hdl.handle.net/10133/5337 DNA is damaged by many agents in the environment and this affects many cellular processes, including DNA replication. The present thesis uses a multiscale computational modeling approach to study the intrinsic conformational and base-pairing preferences of flexible O6-G and O2-T alkyl DNA lesions, and the corresponding properties within DNA duplexes and polymerase active sites. Specifically, the replication of O6-benzylguanine (Bz-G) by a prototypical DNA polymerase, DNA polymerase IV, as well as the replication of the tobacco-derived carcinogens, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), and O2-[4-oxo-4-(3-pyridyl)butyl] thymine (POB-T), by human DNA polymerases η and κ, were investigated. This work uncovers structural bases for the reported lesion mutagenicity and biological processing. Additionally, a consistent theoretical framework was used to provide insight into the previously unidentified general base for the nucleotidyl transfer reaction catalyzed by polymerase η. Overall, this thesis emphasizes the complex interplay between many factors that are required to replicate damaged DNA. en_US Lethbridge, Alta. : University of Lethbridge, Department of Chemistry and Biochemistry Arts and Science Department of Chemistry and Biochemistry Thesis (University of Lethbridge. Faculty of Arts and Science) DNA damage -- Research DNA replication -- Research DNA replication -- Computer simulation DNA damage -- Computer simulation Mutagenesis DNA adducts Cellular control mechanisms DNA repair -- Research DNA repair -- Computer simulation computational chemistry damaged DNA replication flexible DNA lesions lesion mutagenicity tobacco lesions Computational insights into the molecular basis for the replication of flexible tobacco-derived DNA lesions Thesis Ph.D 0494 0487 Yes No open.access