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Title page for ETD etd-08292016-105632

Type of Document Dissertation
Author Howard, Gregory Caleb
URN etd-08292016-105632
Title The role of the ubiquitin-proteasome system in Gcn4 target gene transcription
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
David M. Miller, III Committee Chair
P. Anthony Weil Committee Member
Roland W. Stein Committee Member
Ryoma Ohi Committee Member
  • ubiquitin
  • proteasome
  • transcription
  • Gcn4
  • Cdc48
  • chromatin
Date of Defense 2016-08-09
Availability unrestricted
The ubiquitin–proteasome system (UPS) influences gene transcription in multiple ways. One way in which the UPS impacts transcription centers on transcriptional activators, the function of which can be stimulated by components of the UPS that also trigger their destruction. Activation of transcription by the yeast activator Gcn4, for example, is attenuated by mutations in the ubiquitin-ligase that mediates Gcn4 ubiquitylation or by inhibition of the proteasome, leading to the idea that ubiquitin-mediated proteolysis of Gcn4 is required for its activity. Here, I probe the steps in Gcn4 activity that are perturbed by disruption of the UPS. I show that the ubiquitylation machinery and the proteasome control different steps in Gcn4 function, and that proteasome activity is required for the ability of Gcn4 to bind to its target genes in the context of chromatin. Curiously, the impact of proteasome inhibition on Gcn4 activity is suppressed by mutations in the ubiquitin-selective chaperone Cdc48, revealing that proteolysis per se is not required for Gcn4 activity. My data highlights the role of Cdc48 in controlling promoter occupancy by Gcn4 and support a model in which ubiquitylation of activators—not their destruction—is important for function.
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