All ETDs from UAB

Advisory Committee Chair

Keith E Giles

Advisory Committee Members

David A Schneider

Rui Zhao

Hao Jiang

Nicole Riddle

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The Central Dogma of molecular biology describes the process by which genetic material is faithfully converted into functional molecules across all domains of life. Originally, RNA was solely understood as an intermediate in this process. However, mounting evidence over the past 50 years has made clear that RNA have diverse functional roles as a class of molecule termed non-coding RNA. Two of the first described non-coding RNA have essential roles within the Central Dogma, itself: ribosomal RNA (rRNA) and transfer RNA (tRNA). These two non-coding RNA are highly abundant, collectively accounting for up to 90% of the total transcript in any given cell, and are synthesized by the specialized nuclear RNA polymerases, RNA polymerase I (Pol I) and III (Pol III), respectively. While these RNA serve critical roles in translation, it has become clear that they also possess vast regulatory potential outside of translation. My dissertation research has sought to investigate the synthesis of these non-coding RNA in both cancer cell lines and pluripotent cell types, with a focus on gene regulation by Pol I and Pol III. In these chapters, I present evidence that (1) the RNA interference protein, AGO2, directly interacts with nascent tRNA and facilitates in cis gene repression of nearby mRNA genes; (2) rRNA synthesis is reduced upon differentiation with ACTIVIN A and that direct inhibition of Pol I is capable of inducing the loss of pluripotency; and (3) the activity of certain tRNA genes is significantly changed upon differentiation with ACTIVIN A and these changes correlate with altered translational needs of the cell.

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