Deciphering novel UPS regulation of Sgf73/ataxin-7 in controlling SAGA and associated functions in gene expression

Sgf73/ataxin-7 is a key component of an evolutionarily conserved transcriptional co-activator SAGA (Spt-Ada-Gcn5-Acetyltransferase) with two distinct enzymatic activities for chromatin modifications, and is up- and downregulated in cancer and other diseases such as eye and neurological disorders. Therefore, it is crucial to understand the regulatory networks lying upstream of Sgf73 towards understanding the pathogenesis of these diseases with targeted therapeutic interventions. However, it remains largely unknown how Sgf73 is regulated. In view of this, we carried out a set of experiments which demonstrated ubiquitylation and proteasomal degradation of Sgf73, thus revealing a novel UPS (Ubiquitin-proteasome system) regulation of Sgf73. However, the E3 ubiquitin ligase involved in such regulation of Sgf73 is yet unknown. Further, the physiological relevance of such regulation of Sgf73 on SAGA’s integrity and functions in controlling gene expression remains largely elusive. Moreover, other factors such as ubiquitin protease and conjugase involved in Sgf73 ubiquitylation and proteasomal degradation are not yet known. Answers to these important questions would fundamentally establish novel UPS regulation of Sgf73 in orchestrating gene expression, thus greatly advancing the field of gene regulation. In addition, these results would have significant impact on understanding the pathogenesis of cancer and other diseases such as eye and neurological disorders and future therapeutic development, since Sgf73 is associated with these diseases. Therefore, we propose to address above questions in this application. Specifically, we aim to (i) identify E3 ubiquitin ligase involved in Sgf73 ubiquitylation and proteasomal degradation, (ii) determine ubiquitylation site on Sgf73, (iii) determine the physiological relevance/roles of Sgf73 ubiquitylation and proteasomal degradation in regulation of SAGA’s integrity and functions in gene expression in controlling cellular health, and (iv) identify ubiquitin conjugase, ubiquitin protease and other factors involved in regulation of Sgf73 ubiquitylation and proteasomal degradation with associated functions. Collective results would identify new factors involved in regulation of Sgf73 with roles in controlling SAGA and gene expression in maintaining cellular functions, thus fundamentally advancing our understanding of gene regulation by UPS with implications in human health. Project Number: 1R15CA290595-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Sukesh Bhaumik | Institution: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE, CARBONDALE, IL | Award Amount: $445,500 | Activity Code: R15 | Study Section: Special Emphasis Panel[ZRG1 CDB-J (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11043599