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Title page for ETD etd-01112016-154040

Type of Document Dissertation
Author McCann, Tyler Scott
URN etd-01112016-154040
Title Elucidation of the Biological Function of the RPC Family Ubiquitin Ligase Asr1
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Dr. Stephen Hann Committee Chair
Dr. Melanie Ohi Committee Member
Dr. Todd Graham Committee Member
Dr. Tony Weil Committee Member
  • ubiquitin
  • silencing
  • RNA polymerase II
  • transcription
  • chromatin
Date of Defense 2015-12-09
Availability unrestricted
Proper regulation of gene transcription is an essential process for any cell. Failure to precisely control the procedure of transcription can lead to developmental defects, disease, and even death. Within the last 20 years, ubiquitin, and other factors of the ubiquitin proteasome system have been shown to be extensively involved in the control of various steps of transcription. The Saccharomyces cerevisiae protein Asr1, is the defining member of an evolutionarily conserved set of proteins that contain a RING finger, a PHD finger, and a domain that binds the C-terminal repeat region of RNA polymerase II (RNAPII) called the RPC protein family. Asr1 is recruited to RNAPII in response to hyperphosphorylation of its regulatory C-terminal tail. Once bound, Asr1 oligoubiquitylates at least two subunits of RNAPII, leading to the ejection of the dissociable heterodimer Rpb4 and Rpb7, as well as the transcriptional inactivation of the polymerase complex. Despite the clear biochemical effects Asr1 has on RNAPII, a biological role for Asr1 within the cell has remained elusive. Within this dissertation, I present evidence that Asr1 is involved in the silencing of transcription of genes located at subtelomeric regions. Asr1 has been observed to associate with subtelomeric chromatin, and disruption of the ability of Asr1 to ubiquitylate RNAPII induces transcription at these regions. Asr1 also physically associates with Ubp3, a ubiquitin specific protease with a known role in the regulation of silent chromatin at sub-telomeric regions. I show that Asr1 and Ubp3 have antagonistic roles in both the ubiquitylation of RNAPII as well as the transcription of genes located in telomere proximal regions. The evidence presented in this dissertation reveal the importance of non-proteolytic ubiquitylation in the control of transcription, but also sheds light on a poorly understood family of eukaryotic ubiquitin-ligases.
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