Role of the Ubiquitin-Proteasome System in Regulation of Transcription Factors
Publisher
University of Tennessee at Chattanooga
Place of Publication
Chattanooga (Tenn.)
Abstract
The ubiquitin–proteasome system (UPS) is a central regulator of transcription factor (TF) stability, activity, and chromatin dynamics in eukaryotic cells. Through the coordinated action of E1, E2, and E3 enzymes, ubiquitin is conjugated to substrate proteins, generating signals that direct either proteasomal degradation or non-proteolytic functional modulation. K48-linked polyubiquitin chains predominantly target transcriptional regulators for degradation by the 26S proteasome, whereas mono-ubiquitination and alternative ubiquitin linkages mediate transcriptional regulation without proteolysis.
This narrative review synthesizes current knowledge on UPS-mediated control of transcription, with a focus on transcription initiation, elongation, and chromatin remodeling. Evidence indicates that UPS-mediated turnover of key factors such as TAF7, MYC, SGF73, Paf1, the SPT16 subunit of FACT, and RNA polymerase II enables dynamic regulation of transcriptional machinery. In parallel, the proteasome—particularly the 19S regulatory particle—exhibits non-canonical functions at active genes, coordinating transcriptional output through interactions with histone H2B monoubiquitination.
Deubiquitinases further refine transcriptional responses by reversing ubiquitin signals and fine-tuning TF stability and activity. Collectively, the UPS provides precise, gene-specific, and temporal control of transcription and chromatin states. Dysregulation of UPS components is strongly implicated in cancer, neurodegeneration, and other major diseases. Emerging therapeutic strategies, including proteasome inhibitors, deubiquitinase inhibitors, and PROTAC-based E3 ligase modulators, underscore the translational potential of targeting this pathway. Future research should prioritize selective reprogramming of UPS-dependent transcriptional networks for therapeutic intervention. Overall, these findings position the UPS as a central and druggable hub for transcriptional and chromatin regulation in health and disease.
Document Type
abstracts (summaries)
Language
English
Rights
http://rightsstatements.org/vocab/InC/1.0/
License
http://creativecommons.org/licenses/by/4.0/
Recommended Citation
Wood, Emily; Osborn, Morgan; and Ferdoush, Jannatul, "Role of the Ubiquitin-Proteasome System in Regulation of Transcription Factors". ReSEARCH Dialogues Conference proceedings. https://scholar.utc.edu/research-dialogues/2026/presentations/11.
Role of the Ubiquitin-Proteasome System in Regulation of Transcription Factors
The ubiquitin–proteasome system (UPS) is a central regulator of transcription factor (TF) stability, activity, and chromatin dynamics in eukaryotic cells. Through the coordinated action of E1, E2, and E3 enzymes, ubiquitin is conjugated to substrate proteins, generating signals that direct either proteasomal degradation or non-proteolytic functional modulation. K48-linked polyubiquitin chains predominantly target transcriptional regulators for degradation by the 26S proteasome, whereas mono-ubiquitination and alternative ubiquitin linkages mediate transcriptional regulation without proteolysis.
This narrative review synthesizes current knowledge on UPS-mediated control of transcription, with a focus on transcription initiation, elongation, and chromatin remodeling. Evidence indicates that UPS-mediated turnover of key factors such as TAF7, MYC, SGF73, Paf1, the SPT16 subunit of FACT, and RNA polymerase II enables dynamic regulation of transcriptional machinery. In parallel, the proteasome—particularly the 19S regulatory particle—exhibits non-canonical functions at active genes, coordinating transcriptional output through interactions with histone H2B monoubiquitination.
Deubiquitinases further refine transcriptional responses by reversing ubiquitin signals and fine-tuning TF stability and activity. Collectively, the UPS provides precise, gene-specific, and temporal control of transcription and chromatin states. Dysregulation of UPS components is strongly implicated in cancer, neurodegeneration, and other major diseases. Emerging therapeutic strategies, including proteasome inhibitors, deubiquitinase inhibitors, and PROTAC-based E3 ligase modulators, underscore the translational potential of targeting this pathway. Future research should prioritize selective reprogramming of UPS-dependent transcriptional networks for therapeutic intervention. Overall, these findings position the UPS as a central and druggable hub for transcriptional and chromatin regulation in health and disease.