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Chemical and Genetic Regulation of Nuclear Receptor 5A (NR5A) Sumoylation

  • Author(s): Gertz, Karmela Ramos
  • Advisor(s): Ingraham, Holly A
  • et al.
Abstract

ABSTRACT

SUMO-modification of nuclear proteins has profound effects on gene expression. While inhibitors of in vitro sumoylation exist, drugs that affect in vivo protein sumoylation have yet to be described. Using a gene expression- and cell-based screen and the Liver Receptor Homolog 1 (LRH-1, NR5A2), we identify the polyphenol tannic acid (TA) as a potent, detergent-resistant inhibitor in vitro. TA can inhibit sumoylation of multiple substrates and also reduces levels of general sumoylation. Further, TA appears to be more potent and more effective than other sumoylation inhibitors. Importantly, we demonstrate that TA can greatly diminish hLRH-1 sumoylation in multiple cell models, robustly activating SUMO-sensitive transcription and enriching chromatin occupancy of hLRH-1. Further studies using either TA or the SUMO-less mutants of LRH-1 and its homolog, SF-1, reveal that de novo genome-wide chromatin occupancy is relatively unchanged. However, preliminary suggest that protein-protein interaction with a specific binding partner can be enhanced by SF-1 sumoylation. Our findings show that pharmacological and genetic approaches to probe sumoylation begin to provide insights into how post translational modification of proteins is used to fine tune gene expression.

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