Biomedical Sciences ETDs

Publication Date

Fall 12-17-2022

Abstract

Arsenite exposure leads to the retention of UV-induced DNA damage, thus burdening translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and is implicated in homologous recombination. It contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Results from this study reveal arsenite binding to both zinc fingers of Rad18 and a corresponding loss of domain function. Importantly, arsenite inhibited Rad18 RING-dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage. Further analysis demonstrated multiple effects of arsenite, including the reduction in the nuclear localization and UV-induced chromatin recruitment of Rad18. Arsenite and Rad18 knockdown in UV exposed keratinocytes significantly increased markers of replication stress and DNA strand breaks to a similar degree, suggesting arsenite mediates its effects through Rad18. Altogether, this dissertation supports a mechanism by which arsenite inhibits TLS through the altered activity and regulation of Rad18.

Keywords

Arsenic, cocarcinogenesis, DNA repair, Rad18, translesion synthesis, zinc finger

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Laurie Hudson

Second Committee Member

Dr. Mary Ann Osley

Third Committee Member

Dr. Alan Tomkinson

Fourth Committee Member

Dr. Debra MacKenzie

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