Computational insights into the molecular basis for the replication of flexible tobacco-derived DNA lesions

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dc.contributor.authorWilson, Katie A.
dc.contributor.authorUniversity of Lethbridge. Faculty of Arts and Science
dc.contributor.supervisorWetmore, Stacey D.
dc.date.accessioned2019-04-24T17:18:01Z
dc.date.available2019-04-24T17:18:01Z
dc.date.issued2018
dc.degree.levelPh.Den_US
dc.description.abstractDNA 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
dc.embargoNoen_US
dc.identifier.urihttps://hdl.handle.net/10133/5337
dc.language.isoen_USen_US
dc.proquest.subject0494en_US
dc.proquest.subject0487en_US
dc.proquestyesYesen_US
dc.publisherLethbridge, Alta. : University of Lethbridge, Department of Chemistry and Biochemistryen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.relation.ispartofseriesThesis (University of Lethbridge. Faculty of Arts and Science)en_US
dc.subjectDNA damage -- Researchen_US
dc.subjectDNA replication -- Researchen_US
dc.subjectDNA replication -- Computer simulationen_US
dc.subjectDNA damage -- Computer simulationen_US
dc.subjectMutagenesisen_US
dc.subjectDNA adductsen_US
dc.subjectCellular control mechanismsen_US
dc.subjectDNA repair -- Researchen_US
dc.subjectDNA repair -- Computer simulationen_US
dc.subjectcomputational chemistryen_US
dc.subjectdamaged DNA replicationen_US
dc.subjectflexible DNA lesionsen_US
dc.subjectlesion mutagenicityen_US
dc.subjecttobacco lesionsen_US
dc.titleComputational insights into the molecular basis for the replication of flexible tobacco-derived DNA lesionsen_US
dc.typeThesisen_US
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