Application of a small molecule inhibitor to discover functions of O-GlcNAc transferase in mammalian cells

Abstract

In this dissertation, I discuss how a recently developed small molecule inhibitor of O-GlcNAc transferase (OGT) has enabled the discovery of previously undocumented facets of OGT function. In the first chapter, I introduce O-GlcNAc, current hypotheses for its function in cells, and existing strategies used to probe it. In the second chapter, I present experiments we performed to identify protein factors regulating the splicing of the OGT detained intron and show that nuclear localization of OGT is required for this splicing response. In the third chapter, I described a genetic screen we conducted to identify genetic interactors of OGT, which led us to uncover OGT’s regulation of lipid homeostasis in cells. The dataset resulting from the screen are fertile grounds for further exploration into how OGT regulates various pathways. In the end, I present an opportunity to rethink of the function of OGT and how we generate models for its function.