Research thoughts by:

Daniel Dempsey

Current Research Projects

7/10/2023

The mission of my laboratory is to understand the basic biological mechanisms of proteins essential to human health and cancer biology. We use chemical, semi-synthetic, biophysical, and cellular approaches to elucidate mechanisms for how post-translational modifications (PTMs) regulate protein function. We are also interested in advancing new chemical strategies to investigate PTMs, protein function, and cancer biology. My focus is on understanding the function and regulation of ubiquitin, deubiquitinases, and RNA-modifying proteins, which are emerging as attractive therapeutic targets in several cancers. Our goal is that understanding these mechanisms will help pave the way for the rational design of new therapies for cancer treatment. It is projected that there will be almost two million new cancer cases and over 600,000 deaths in the United States in 2023, making it the 2nd leading cause of death. Therefore, a better understanding of the molecular devices that cancer uses to promote its carcinogenesis, protects its key drivers, and discovering new therapeutic targets are desperately needed. The two projects below summarize our approach to addressing these major gaps in knowledge. 

Project #1. Over the past two decades, there has been immense interest in targeting the ubiquitin-proteasome system (UPS) with the emergence of PROTACs, proteasome inhibitors, and inhibitors of ubiquitin ligases and deubiquitinases (DUBs); however, our understanding of this system and the insight necessary to exploit its vulnerabilities in cancer are severely lacking, but a detailed biochemical, structural, proteomic, and regulatory analysis of the core contributors can provide rules that govern this process. We hypothesize that ubiquitin has a much more elegant regulatory role than simply serving as a “molecular stamp” for protein degradation and that DUBs directly target and stabilize oncoproteins in cancer. Therefore, we are developing new chemical approaches to decipher the ubiquitin code, understand the key molecules that stabilize oncoproteins, and identify new weaknesses within the code that we may target with new therapeutics. Overall, completing this project will provide a deeper understanding of how ubiquitin influences the function of these proteins, and we will discover the cellular machinery that cancer abuses to stabilize the presence of oncoproteins.

Project #2. The past decade has seen an emergence of the “epitranscriptome” field with the discovery of readers, writers, and easers of mRNA modifications, establishing the tunability of gene expression by -transcriptional modifications. Defects in the epitranscriptome may lead to diseases, including cancer. For example, it has been well-established that a delicate balance of mRNA m6A is required to maintain normal hematopoiesis, where its dysregulation leads to leukemogenesis. Understanding the “code” and the enzymatic processes that govern RNA modifications are key to revealing pathophysiological mechanisms and developing novel therapeutics. RNA modifying enzymes are chemically altered by PTMs, but our understanding of how these marks regulate their function, modulate the potency of novel therapeutics, and their impact on gene expression is a major gap in our knowledge. Therefore, we plan to use our protein chemical toolset to investigate how these modifications can influence the activities of these proteins while also discovering the cellular machinery that cancer abuses to stabilize their presence.