All ETDs from UAB

Advisory Committee Chair

David A Schneider

Advisory Committee Members

Maaike Everts

Natalia Kedishvili

Susan Bellis

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

My graduate research has focused on understanding the elongation kinetics of RNA polymerase I (Pol I), the enzyme responsible for synthesizing ribosomal RNA (rRNA), and defining how inhibition of ribosome biogenesis may be used as a cancer therapeutic strategy. Here, I have defined key biophysical features of Pol I and I have expanded the field’s understanding of Pol I elongation by: 1) characterizing the enzymatic properties of Pol I by mutational analysis of the polymerase itself, and by 2) elucidating the role of DNA sequence on Pol I arrest and nucleolytic cleavage activity. In recent years, Pol I has become an attractive target for cancer therapeutics, as enhanced ribosome biogenesis is necessary for the rapid growth and proliferation of cancer cells. I have demonstrated that ribosome biogenesis inhibition by a novel inhibitor, RBI2 (ribosome biogenesis inhibitor 2) specifically decreases cancer cell growth and proliferation, likely by increasing premature rRNA turnover. Collectively, my studies on Pol I’s enzymatic properties have resulted in a better understanding of the relationship between cancer cell growth and ribosome biogenesis. As a whole, my thesis research has resulted in a more detailed understanding of RNA polymerase I (Pol I) elongation kinetics and it has further validated inhibition of ribosome biogenesis as a promising cancer chemotherapeutic target.

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