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 (PTM) 之一， 与磷酸化和泛素化相当，对应于蛋白质精氨酸甲基转移酶（PRMT）。 产生三种甲基化精氨酸残基的“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) 是主要的 I 型酶。 催化 ADMA，而 PRMT5 是生成 SDMA 的主要 II 型酶。 甲基化许多下游底物以调节各种基本细胞过程，例如 经常观察到 PRMT1/5 的转录、DNA 修复和细胞信号转导。 与许多其他癌症一样，它与癌症患者的不良预后和生存相关。 PTM，精氨酸甲基化是一个可逆过程，脱甲基酶充当去除甲基的“橡皮擦”。 此外，称为“读取器”的效应蛋白与甲基精氨酸结合并介导。 尽管在过去的三十年中人们已经做出了巨大的努力，但仍存在一些问题。 精氨酸甲基化领域仍然存在许多悬而未决的问题/差距。 上游信号/调节器有哪些特定的精氨酸脱甲基酶？ 精氨酸甲基化蛋白质？在本提案中，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 定位、激活和功能，揭示了 PRMT1 的新型上游刺激/调节器。 剖析泛素化途径在 PRMT5 调节中的作用，定义精氨酸之间的新型相互作用 甲基化和泛素化项目 3 将鉴定新的去甲基化酶和精氨酸甲基化的读者， 我们将使用一系列补充方法，包括填补精氨酸甲基化领域的关键空白。 我们的生物化学、质谱 (MS) 分析、分子和细胞生物学以及小鼠模型 我们的短期目标是通过完成来增进我们对精氨酸甲基化生物学的理解。 拟议的研究，长期目标是确定针对精氨酸的新靶点/策略/抑制剂 为了实现这些目标，我将致力于这个项目。 51%“研究工作”。