Regulatory Mechanisms of Arginine Methylation

精氨酸甲基化的调控机制

• 批准号: 10670965
• 负责人: Wenjian Gan
• 金额: $ 37.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670965
• 关键词: Address; Amino Acids; Arginine; Binding; Biochemistry; Biology; Cancer Patient; Cell physiology; Cells; DNA Repair; Enzymes; Genetic Transcription; Goals; Malignant Neoplasms; Mediating; Methods; Methylation; Molecular; Molecular and Cellular Biology; N,N-dimethylarginine; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Process; Prognosis; Protein Methylation; Protein-Arginine N-Methyltransferase; Proteins; Reader; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stimulus; Ubiquitination; cancer survival; cancer therapy; dimethylarginine; inhibitor; methyl group; mouse model; novel; programs

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”.

摘要 精氨酸甲基化是最常见的翻译后修饰（PTM）之一， 类似于磷酸化和泛素化。蛋白质精氨酸甲基转移酶（PRMT）对应于 生成三种类型的甲基化精氨酸残基的“写入器”：单甲基精氨酸（MMA）、不对称精氨酸 二甲基精氨酸（ADMA）和对称二甲基精氨酸（SDMA）。PRMT 1是主要的I型酶， PRMT 5是催化ADMA的主要II型酶，而PRMT 5是产生SDMA的主要II型酶。PRMT 1/5 甲基化许多下游底物以调节各种基本细胞过程，例如 转录、DNA修复和细胞信号转导。经常观察到PRMT 1/5的失调 在各种癌症中，并且与癌症患者的不良预后和存活相关。像许多其他 PTM，精氨酸甲基化是一个可逆的过程。脱甲基酶作为“橡皮擦”， 从目标蛋白质。此外，被称为“阅读器”的效应蛋白与甲基精氨酸结合， 细胞中的信号转导。尽管在过去三十年中作出了巨大努力， 在精氨酸甲基化领域仍有许多悬而未决的问题/空白。PRMT活性如何受 上游信号/调节器？是否存在特定的精氨酸脱甲基酶？读者们对众多的 精氨酸甲基化蛋白质？在本提案中，我们将探讨三个项目来解决这些问题。 项目1将阐明氨基酸调节PRMT 1亚细胞的分子机制 定位，激活和功能，揭示了一种新的上游刺激/调节PRMT 1。项目2将 分析了泛素化途径在PRMT 5调控中的作用，定义了精氨酸与 甲基化和泛素化。项目3将确定新的脱甲基酶和精氨酸甲基化的读者， 填补了精氨酸甲基化领域的关键空白。我们将使用一系列补充方法，包括 生物化学，质谱（MS）分析，分子和细胞生物学，以及小鼠模型，在我们的 问题研究我们的短期目标是通过完成精氨酸甲基化生物学的研究， 拟定的研究和对数期目标是确定靶向精氨酸的新靶标/策略/抑制剂 甲基化信号通路用于癌症治疗。为了实现这些目标，我将致力于这一计划 51%是“研究工作”。