Transcriptional regulation and ubiquitin-mediated proteolysis are two processes that feature prominently in the control of cell growth and development. Consistent with their pivotal roles in maintaining cellular homeostasis, deregulation of both transcription and ubiquitin-mediated protein destruction lies at the heart of a variety of human diseases, including cancer. At first blush, these two processes have apparently very little in common-transcription is the first step in the life of any protein;proteolysis is the last. Despite the disparate nature of these processes, however, a growing body of evidence suggests that components of the ubiquitin-proteasome system are directly involved in the regulation of gene expression. The connection of these processes reveals a previously unanticipated level of transcriptional control that we are anxious to explore. This proposal defines a research strategy to investigate how ubiquitin-dependent processes regulate the activity of three key players in transcriptional regulation-transcriptional activators, RNA polymerase, and histones. These studies will be complemented with a highly-integrated analysis of the role of proteasome components in gene activation. To achieve this objective, we will employ a combination of genetic and biochemical approaches using the model organism Saccharomyces cerevisiae. We will study how ubiquitylation of the prototypical yeast activator Gal4 connects transcriptional activation to events required for co-transcriptional pre-messenger RNA processing. We will investigate how ubiquitylation of the largest subunit of RNA polymerase II regulates polymerase activity and subunit composition, and how ubiquitylation of histone H2B modulates histone dynamics and interaction of chromatin with the nuclear environment. And, finally, we will study how proteasome subunits are recruited to chromatin and their function in both gene activation and transcriptional silencing. Results of these studies will provide valuable insight into how transcription and the ubiquitin-proteasome systems intersect, and will serve as a paradigm for our understanding of this new dimension in transcriptional control. Importantly, our work will also provide an intellectual framework for understanding how these processes contribute to human disease, and offers the potential to identify ways to regulate aberrant transcription by modulating the activity of the ubiquitin system;a strategy that could very-well form the basis of improved cancer therapies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Tompkins, Laurie
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Howard, Gregory C; Tansey, William P (2016) Interaction of Gcn4 with target gene chromatin is modulated by proteasome function. Mol Biol Cell 27:2735-41
McCann, Tyler S; Guo, Yan; McDonald, W Hayes et al. (2016) Antagonistic roles for the ubiquitin ligase Asr1 and the ubiquitin-specific protease Ubp3 in subtelomeric gene silencing. Proc Natl Acad Sci U S A 113:1309-14
Bonizec, Mélanie; Hérissant, Lucas; Pokrzywa, Wojciech et al. (2014) The ubiquitin-selective chaperone Cdc48/p97 associates with Ubx3 to modulate monoubiquitylation of histone H2B. Nucleic Acids Res 42:10975-86
Galligan, James J; Rose, Kristie L; Beavers, William N et al. (2014) Stable histone adduction by 4-oxo-2-nonenal: a potential link between oxidative stress and epigenetics. J Am Chem Soc 136:11864-6
McCann, Tyler S; Tansey, William P (2014) Functions of the proteasome on chromatin. Biomolecules 4:1026-44
Geng, Fuqiang; Wenzel, Sabine; Tansey, William P (2012) Ubiquitin and proteasomes in transcription. Annu Rev Biochem 81:177-201
Geng, Fuqiang; Tansey, William P (2012) Similar temporal and spatial recruitment of native 19S and 20S proteasome subunits to transcriptionally active chromatin. Proc Natl Acad Sci U S A 109:6060-5
Howard, Gregory C; Collins, Galen A; Tansey, William P (2011) Letter to the Editor. Yeast :
Zheng, Siyuan; Tansey, William P; Hiebert, Scott W et al. (2011) Integrative network analysis identifies key genes and pathways in the progression of hepatitis C virus induced hepatocellular carcinoma. BMC Med Genomics 4:62
Leung, Amy; Cajigas, Ivelisse; Jia, Peilin et al. (2011) Histone H2B ubiquitylation and H3 lysine 4 methylation prevent ectopic silencing of euchromatic loci important for the cellular response to heat. Mol Biol Cell 22:2741-53

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