Transfer RNA has long been known to be essential for protein synthesis. Only relatively recently has its role as signal molecule been examined. Of particular interest is the role of uncharged tRNA in cellular regulation, specifically metabolism. Changes in tRNA charging, or aminoacylation, can occur very rapidly making it an ideal method for intracellular signaling.
This thesis aims to explore the regulatory role of tRNA in S. cerevisae, focusing on how tRNA can regulate metabolism. The first part focuses on how the Gcn2/Gcn4 translation regulation pathway is activated by uncharged tRNAs. The Gcn2/Gcn4 pathway is part of a global stress response system that is activated by an increase in uncharged tRNAs. This is the first examination of how the charging levels of all tRNAs change as the cell adapts to various stresses. I expand on this and examine how Gcn2 regulation can alter metabolic flux in the cell, focusing on aromatic amino acid biosynthesis and nitrogen metabolism. These two pathways are of particular interest since they are highly dependent on Gcn2 for regulation. Finally the role of tRNA in regulating proteasome activity is examined. By selectively targeting key metabolic proteins the proteasome can rapidly alter the metabolic profile of the cell. Previous work in mammalian proteasomes demonstrated the existence of a tRNA dependent regulation system. In this work I demonstrate a similar system exists in yeast and begin to examine how tRNA can regulate the proteasome.
The work presented here clarifies and expands tRNA’s role in metabolic regulation. It presents a new and unexpectedly complex model for tRNA activation of the GCN2 protein kinase. tRNA’s role as a proteasome regulator is also more firmly established by this research. Overall the research presented in this thesis supports the emerging idea that tRNA part of an essential and complex cellular signaling system.
|Commitee:||Crosson, Sean, Keenan, Robert, Staley, Jonathan|
|School:||The University of Chicago|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Illinois|
|Source:||DAI-B 71/07, Dissertation Abstracts International|
|Keywords:||Cellular stress, Metabolism, Proteasomes, tRNA|
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