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Principal Investigator: Wenjian Gan
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $377,500
Funding agency: National Institute of General Medical Sciences
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”.
Terms: <Address><Amino Acids><Arginine><Arginine Methylase><Binding><Biochemistry><Biological Chemistry><Biology><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><DNA Damage Repair><DNA Repair><Enzyme Gene><Enzymes><Gene Transcription><Genetic Transcription><Goals><Histone (Arginine) Methyltransferase><Intracellular Communication and Signaling><L-Arginine><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Methods><Methylation><Molecular><Molecular Interaction><Molecular and Cellular Biology><Myelin Basic Protein (Arginine) Methyltransferase><N,N-dimethylarginine><Pathway interactions><Phosphorylation><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Prognosis><Protein Arginine Methyltransferase><Protein Methylase I><Protein Methylation><Protein Methyltransferase I><Protein Modification><Protein Phosphorylation><Protein-Arginine N-Methyltransferase><Proteins><RNA Expression><Reader><Regulation><Research><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Subcellular Process><Transcription><Ubiquitilation><Ubiquitination><Ubiquitinoylation><Unscheduled DNA Synthesis><aminoacid><anti-cancer therapy><asymmetric dimethylarginine><biological signal transduction><cancer survival><cancer therapy><cancer-directed therapy><dimethyl-L-arginine><dimethylarginine><guanidino-N,N-dimethylarginine><inhibitor><malignancy><methyl group><mouse model><murine model><neoplasm/cancer><novel><pathway><programs><social role><ubiquination><ubiquitin conjugation>