Dynamics of Arginine Methylation in Cellular Processes

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Arginine, one of the twenty amino acid building blocks that make up proteins, exhibits the interesting chemical property of bearing a positive charge spread over several atoms that allows it to form unique and important interactions for proteins in cells. Enzymes called protein arginine N-methyltransferases (PRMTs) adds methyl groups onto arginines within the positively charged part of the amino acid to elicit changes in protein function. This arginine methylation, found predominantly in chromatin-associated and RNA-binding proteins, has been shown to play regulatory roles in gene expression, DNA damage repair, RNA metabolism and transport, and signal transduction. Whereas several PRMTs participate in these processes, the functional role other PRMTs and their substrates is less well defined. We address this gap in our knowledge with two aims in our research proposal. First, we have identified using proteomics PRMT2 interacting partners involved in RNA splicing that regulates programmed cell death, and we plan to determine how PRMT2 contributes to this process in cells by increasing or decreasing its expression and measuring changes to spliced RNA and its interactions. Second, we have measured using proteomics global changes to arginine methylation in cells treated with inflammatory stress in an effort to discover responsive protein networks and important PRMT substrates. Following up on these results, we plan to determine the importance of increased substrate methylation observed in NF-kappaB signaling during inflammation, as well as the consequences of other methylation events. We would also like to take advantage of this proteomic method for discovery to look at cell responses to genotoxic and hypoxic stresses as a way to reveal unique and common features within arginine methylation networks between several different types of cell stress. Overall, this work will provide mechanistic insight into how the integration of PRMT activities contributes to cellular programming and ultimately determines cell fate, which will have broad impact in multiple fields of life science research. Trainees supported by this NSERC grant will learn a diverse set of cutting-edge skills in biochemistry and cell biology offered in a research-intensive environment that will help them to succeed in the proposed work and their future scientific careers.**