Regulatory Mechanisms of Arginine Methylation

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Abstract Arginine methylation is one of the most common posttranslational modifications (PTMs), which is comparable to phosphorylation and ubiquitination. Protein arginine methyltransferases (PRMTs) correspond to “writers” that generate three types of methylated arginine residues: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). PRMT1 is the main type I enzyme for catalyzing ADMA, while PRMT5 is the predominant type II enzyme for generating SDMA. PRMT1/5 methylates many downstream substrates to regulate a variety of fundamental cellular processes, such as transcription, DNA repair and cell signaling transduction. Deregulation of PRMT1/5 is frequently observed in various cancers and is correlated with poor prognosis and survival of cancer patients. Like many other PTMs, arginine methylation is a reversible process. Demethylases function as “erasers” to remove methyl groups from targeted proteins. In addition, effector proteins called “reader” bind to methylarginine and mediate signals transduction in cells. Although tremendous efforts have been made in the past three decades, there are still many outstanding questions/gaps in the field of arginine methylation. How is PRMT activity regulated by upstream signals/regulators? Are there specific arginine demethylases? What are the readers for numerous of arginine methylated proteins? In this proposal, we will explore three projects to address these questions. Project 1 will elucidate the molecular mechanism by which amino acids regulate PRMT1 subcellular localization, activation, and function, revealing a novel upstream stimulus/regulator of PRMT1. Project 2 will dissect roles of the ubiquitination pathway in regulation of PRMT5, defining a novel interplay between arginine methylation and ubiquitination. Project 3 will identify novel demethylases and readers of arginine methylation, filling the key gap in the field of arginine methylation. We will use a range of complementary methods including biochemistry, mass spectrometric (MS) analysis, molecular and cellular biology, and mouse models in our studies. Our short-term goal is to advance our understanding of arginine methylation biology by completing proposed studies, and log-term goal is to identify novel targets/strategies/inhibitors to target arginine methylation signaling pathway for cancer therapy. To achieve these goals, I will be committed to this program at 51% “research effort”.