Biomedical Sciences ETDs

Publication Date

Spring 3-21-2023

Abstract

Half of all the eukaryotic nuclear genome is synthesized as Okazaki fragments on the lagging strand at the replication fork. Okazaki fragment synthesis begins with repeated production of short RNA-DNA primers synthesized by the DNA Polymerase α (Pol α)-primase complex. The primer terminus is recognized by Replication Factor C (RFC) which then loads the sliding clamp protein, proliferating cell nuclear antigen (PCNA), resulting in the recruitment of DNA Polymerase δ (Pol δ) which carries out the gap filling DNA synthesis displacing the 5’ end of the preceding Okazaki fragment which is cleaved by Flap Endonuclease 1 (FEN-1), and ultimately the joining of Okazaki fragments by DNA ligase I (LigI) to generate a continuous strand. Thus, lagging strand DNA replication is a complex process involving the coordinated action of multiple interacting proteins. Alterations in Okazaki fragment metabolism could generate aberrant replication intermediates eventually resulting in cytotoxic single and double strand DNA breaks. With the identification of LigI deficiency syndromes in humans and LigI emerging as a potential therapeutic target in ovarian cancer, studying the mechanisms of lagging strand DNA replication will assist in understanding the disease pathogenesis as well as establishing LigI as a druggable target in cancer therapy.

Keywords

DNA replication and repair, DNA Ligase I

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Alan E Tomkinson

Second Committee Member

Dr. Mary Ann Osley

Third Committee Member

Dr. Hua-Ying Fan

Fourth Committee Member

Dr. Sarah F Adams

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