Date of Award

1-1-2011

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xix, 136 pages) : Pillustrations (some color)

Dissertation/Thesis Chair

Thomas J Begley

Committee Members

Richard Zitomer, Douglas Conklin, Julio Aguirre-Ghiso, Erasmus Schneider, Mike Fasullo

Keywords

Cancer, modifications, translation, Trm9, tRNA, wobble, Transfer RNA, Stress (Physiology), Methyltransferases

Subject Categories

Cell Biology | Genetics | Molecular Biology

Abstract

Cells need to respond appropriately to environmental changes in order to maintain homeostasis. The cellular response to an environmental stress is regulated at transcriptional, translational and post translational levels. The tRNA, which acts as an adaptor molecule between the mRNA and the protein, plays an important role in the translational regulation of cellular responses to stress and is one of the most heavily modified biomolecules. In Saccharomyces cerevisiae , the wobble uracil of the tRNA(3'-UCU-5') Arg, tRNA(3'-UUC-5') Glu and certain other specific tRNAs are modified to 5-methoxycarbonylmethyluridine (mcm5U) and 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) residues by the tRNA methyltransferase 9 (Trm9). Modifications at the wobble base have been hypothesized to affect the binding of the anticodon to the codon and to regulate translational fidelity and elongation. In this dissertation, I have used trm9 cells to delineate the role of Trm9 in the maintenance of translational fidelity and codon dependent translational elongation. Moreover, I have established that the Trm9-based tRNA modifications link translational elongation and fidelity to the unfolded protein and DNA damage responses. I have also demonstrated a link between cell cycle dependent oscillations of mcm 5U levels and Rnr1 protein levels, signifying a novel regulatory role played by the tRNA modifications in the grand scheme of gene expression.

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