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dc.contributor.advisorMichael Volkert, Ph.D.
dc.contributor.authorYu, Lijian
dc.date2022-08-11T08:08:43.000
dc.date.accessioned2022-08-23T16:05:31Z
dc.date.available2022-08-23T16:05:31Z
dc.date.issued2011-06-29
dc.date.submitted2011-08-20
dc.identifier.doi10.13028/q0af-rm56
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31885
dc.description.abstractOxidative stress is a cellular condition where cells are challenged by elevated levels of reactive oxygen species (ROS) that are produced endogenously or exogenously. ROS can damage vital cellular components, including lipid, protein, DNA and RNA. Oxidative damage to DNA often leads to cell death or mutagenesis, the underlying cause of various human disease states. Previously our laboratory discovered that human PC4 gene can prevent oxidative mutagenesis in the bacterium Escherichia coli and that the yeast homolog SUB1 has a conserved function in oxidation protection. In this thesis I examined the underlying mechanisms of PC4’s oxidation protection function. My initial efforts to examine the predicted role of SUB1 in transcription-coupled DNA repair essentially negated this hypothesis. Instead, results from our experiments suggest that PC4 and yeast SUB1 can directly protect genomic DNA from oxidative damage. While testing SUB1’s role in double strand DNA break (DSB) repair, I found the sub1Δ mutant resects DSB ends rapidly but still ligates chromosomal breaks effectively, suggesting that DSB resection is not inhibitory to nonhomologous end-joining, an important DSB repair pathway. Finally, in the course of studying transcription recovery after UV damage, I found UV induces a longer form of RPB2 mRNA and demonstrated that this is caused by alternative polyadenylation of the RPB2 mRNA and that alternative polyadenylation contributes to UV resistance. Based on results of preliminary experiments, I propose that UV activates an alternative RNA polymerase to transcribe RNA POL II mRNA, a novel mechanism to facilitate recovery from inhibition of transcription resulting from UV damage. The hypothetical polymerase switch may account for the UV-induced alternative polyadenylation of the RPB2 mRNA.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectOxidative Stress
dc.subjectDNA Damage
dc.subjectDNA-Binding Proteins
dc.subjectSubtilisins
dc.subjectProprotein Convertases
dc.subjectPolyadenylation
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCells
dc.subjectEnzymes and Coenzymes
dc.subjectGenetic Phenomena
dc.titleThe Role of PC4 in Oxidative Stress: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1546&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/545
dc.legacy.embargo2012-07-06T00:00:00-07:00
dc.identifier.contextkey2178478
refterms.dateFOA2022-08-26T04:52:33Z
html.description.abstract<p>Oxidative stress is a cellular condition where cells are challenged by elevated levels of reactive oxygen species (ROS) that are produced endogenously or exogenously. ROS can damage vital cellular components, including lipid, protein, DNA and RNA. Oxidative damage to DNA often leads to cell death or mutagenesis, the underlying cause of various human disease states. Previously our laboratory discovered that human PC4 gene can prevent oxidative mutagenesis in the bacterium <em>Escherichia coli</em> and that the yeast homolog <em>SUB1</em> has a conserved function in oxidation protection. In this thesis I examined the underlying mechanisms of PC4’s oxidation protection function. My initial efforts to examine the predicted role of <em>SUB1</em> in transcription-coupled DNA repair essentially negated this hypothesis. Instead, results from our experiments suggest that PC4 and yeast <em>SUB1</em> can directly protect genomic DNA from oxidative damage. While testing <em>SUB1</em>’s role in double strand DNA break (DSB) repair, I found the <em>sub1Δ</em> mutant resects DSB ends rapidly but still ligates chromosomal breaks effectively, suggesting that DSB resection is not inhibitory to nonhomologous end-joining, an important DSB repair pathway. Finally, in the course of studying transcription recovery after UV damage, I found UV induces a longer form of <em>RPB2</em> mRNA and demonstrated that this is caused by alternative polyadenylation of the <em>RPB2</em> mRNA and that alternative polyadenylation contributes to UV resistance. Based on results of preliminary experiments, I propose that UV activates an alternative RNA polymerase to transcribe RNA POL II mRNA, a novel mechanism to facilitate recovery from inhibition of transcription resulting from UV damage. The hypothetical polymerase switch may account for the UV-induced alternative polyadenylation of the <em>RPB2</em> mRNA.</p>
dc.identifier.submissionpathgsbs_diss/545
dc.contributor.departmentMicrobiology and Physiological Systems
dc.description.thesisprogramMolecular Genetics and Microbiology


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