Biomedical Sciences ETDs

Publication Date

Spring 4-15-2020

Abstract

Environmental arsenic exposure affects around 100 million people worldwide. Recent evidence shows that arsenite, even at low concentrations, may act as a co-carcinogen, by displacing zinc from the zinc finger motifs of certain DNA repair proteins, leaving them vulnerable to redox modification and loss of protein function. This study probes the physical chemistry underlying arsenite and zinc binding to XPA and PARP1, in the hope of illuminating some of the aspects of protein structure that determine susceptibility to arsenite binding. In this study, dissociation constants are determined for zinc and arsenite binding to peptides corresponding to the C4 zinc finger motif of XPA, and the first C3H1 motif of PARP1, as well as determining rate constants for arsenite-peptide binding. A kinetic advantage for PARP-1zf-1 arsenite binding over XPAzf binding is demonstrated. Additionally, we have identified RPA70 as a novel target of arsenite-mediated redox modification within the nucleotide excision repair pathway.

Keywords

arsenic, zinc, XPA, PARP1, RPA70, Nucleotide excision repair

Document Type

Thesis

Degree Name

Biomedical Sciences

Level of Degree

Masters

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Ke Jian "Jim" Liu

Second Committee Member

Laurie G. Hudson

Third Committee Member

Alan Tomkinson

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