O-GlcNAc Transferase (OGT) is essential for mammalian cell proliferation. OGT is the sole enzyme responsible for adding O-GlcNAc to Ser and Thr residues of thousands of nuclear, cytoplasmic, and mitochondrial proteins. OGT also catalyzes the proteolytic maturation of the essential transcriptional coactivator Host Cell Factor 1 (HCF-1) in the same active site as Ser/Thr glycosylation. Despite decades of study implicating OGT in processes as diverse as transcription, translation, metabolism, and cell cycle progression, it remains unclear which of the many reactions OGT catalyzes are required for cell survival. This question is difficult to address with existing tools, as both chemical inhibition and genetic knockdown will simultaneously inhibit of OGT’s catalytic activities. In order to be able to selectivity inhibit subsets of OGT catalytic activities, we have developed a system to replace OGT with separation-of-function mutants in living cells. We have used this system to determine which class of OGT catalytic activity, HCF-1 cleavage or Ser/Thr O-GlcNAcylation, is required for cell survival. We have further adapted this system to use small-molecule inducible degradation to rapidly separate OGT activities, enabling us to inhibit subsets of OGT activity with high temporal resolution. These tools enable us to use knowledge of OGT structure and biochemistry to selectively inhibit subsets of OGT activity and determine their role in supporting cell survival.<br/>

Why is OGT essential?

2019 Fall National Meeting

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