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”.

抽象的 精氨酸甲基化是最常见的翻译后修饰之一（PTMS），它是 与磷酸化和泛素化相当。蛋白精氨酸甲基转移酶（PRMT）对应于 产生三种类型的甲基化精氨酸残留物的“作家”：单甲基精氨酸（MMA），不对称 二甲基精氨酸（ADMA）和对称二甲基精氨酸（SDMA）。 PRMT1是主要的I酶 催化ADMA，而PRMT5是产生SDMA的主要II型酶。 PRMT1/5 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修复和细胞信号传导翻译。经常观察到PRMT1/5的放松管制 在各种癌症中，与癌症患者的预后不良和存活相关。像许多其他人一样 PTMS，精氨酸甲基化是一个可逆过程。脱甲基酶是去除甲基的“橡皮” 来自靶蛋白的组。此外，效应蛋白称为“读取器”与甲基甲基氨酸结合并介导 尽管在过去的三十年中已经做出了巨大的努力，但仍有 在精氨酸甲基化领域，仍然许多出色的问题/空白。 PRMT活动如何受到 上游信号/调节器？有特定的精氨酸脱甲基酶吗？众多读者是什么 精氨酸甲基化蛋白？在此提案中，我们将探索三个项目来解决这些问题。 项目1将阐明氨基酸调节PRMT1亚细胞的分子机制 揭示了PRMT1的新型上游刺激/调节剂的定位，激活和功能。项目2将 在PRMT5调节中的泛素化途径的剖析作用，定义了精氨酸之间的新型相互作用 甲基化和泛素化。项目3将确定精氨酸甲基化的新型脱甲基酶和读者， 填充精氨酸甲基化领域的钥匙间隙。我们将使用一系列互补方法，包括 生物化学，质谱（MS）分析，分子和细胞生物学以及我们的小鼠模型 研究。我们的短期目标是通过完成精氨酸甲基化生物学的理解 拟议的研究和对数期目标是确定靶向精氨酸的新目标/策略/抑制剂 癌症治疗的甲基化信号通路。为了实现这些目标，我将致力于该计划 以51％的“研究工作”。