All ETDs from UAB

Advisory Committee Chair

David A Schneider

Advisory Committee Members

David M Bedwell

Michael Gray

Anita B Hjelmeland

Marek Napierala

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Ribosome biogenesis is one of the most central processes to cellular growth and metabolism. The synthesis of ribosomal RNA (rRNA) by RNA polymerase I (Pol I) is thought to be rate limiting for ribosome biogenesis, and is therefore subject to extensive regulation. The work presented in this dissertation characterizes two previously undiscovered pathways regulating rRNA synthesis. Due to the direct connection between ribosome biogenesis (and rRNA synthesis) and cellular proliferative potential, Pol I activity is upregulated in cancers. Cancer cells are hypersensitive to inhibition of Pol I, a quality that makes Pol I an attractive target for anticancer therapeutics. The small molecule BMH-21 was discovered as a Pol I inhibitor. BMH-21 is thought to intercalate into the ribosomal DNA, and serves as a physical barrier to Pol I elongation. Interestingly, treatment with BMH-21 triggers the proteasome mediated degradation of the large subunit of Pol I in both higher and lower eukaryotes. The results presented here suggest there is a pathway monitoring Pol I elongation, and when activated, results in the specific degradation of the large subunit of Pol I. The discovery of this pathway provides an exciting new avenue for Pol I research. It was shown over 25 years ago that rRNA synthesis in yeast is repressed during active growth (log phase) presumably in anticipation of an environment that limits growth (stationary phase). The results presented here suggest that quorum sensing is the mechanism regulating this effect. A molecule, smaller than 5 kDa that accumulates in the media of late stationary phase cultures is able to inhibit rRNA synthesis in early log cultures. While we do observe that the large subunit of Pol I degrades during log phase, in a pattern similar to the repression of rRNA synthesis, we show that spent media does not stimulate the degradation of the Pol I large subunit. These results imply that the pathway that is regulated by quorum sensing is distinct than the one activated by BMH-21. The data presented here are the first identification of a quorum sensing pathway regulating ribosome biogenesis in fungi.

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