CONTROL OF EUCARYOTIC FUNCTION BY METHYLATION

通过甲基化控制真核功能

基本信息

批准号：
8413620
负责人：
STEVEN G CLARKE
金额：
$ 49.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-12-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413620
关键词：
4q31 Age Aging Amino Acyl Transfer RNA Area Arginine Attention Bacteria Biochemical Bioinformatics Biological Models Biology Buffaloes Caenorhabditis elegans Cardiovascular Diseases Cell Aging Cell Survival Cells Child Collaborations Complex Coupled DNA DNA Repair Disease Elongation Factor Enzymatic Biochemistry Enzymes Esterification Eukaryotic Cell Event Family Gene Expression Gene Expression Regulation Goals Grant Health Histones Homocysteine Homocystine Human Insulin Intracellular Signaling Proteins Knock-out Laboratories Linguistics Link Longevity Lysine Malignant Neoplasms Mammalian Cell Mammals Maps Mass Spectrum Analysis Metabolic Metabolism Methods Methylation Methyltransferase Modification Mus Nature Neurons Organism Pathology Pathway interactions Physiological Plasma Post-Translational Protein Processing Process Protein Biosynthesis Protein D-Aspartate-L-Isoaspartate Methyltransferase Protein-Arginine N-Methyltransferase Proteins RNA RNA-Protein Interaction Reaction Regulation Regulatory Pathway Resistance Ribosomal Proteins Ribosomes Role S-Adenosylmethionine Side Signal Pathway Signal Transduction Signal Transduction Pathway Site Specificity Stem cells Stress Sum System Testing Toxic Environmental Substances Transfer RNA Transgenic Mice Translations Trypanosoma Work Yeasts arginyllysine cardiovascular risk factor cell age college interest macromolecular assembly man member methyl group methylome nervous system disorder novel overexpression public health relevance repaired response tumor yeast protein

项目摘要

DESCRIPTION (provided by applicant): We will investigate how physiological functions are controlled by methylation reactions, focusing on the enzymes that catalyze the modification of protein arginine, lysine, and isoaspartyl residues. We are especially interested in methyltransferases that are involved in signal transduction and metabolic regulatory pathways where the presence or absence of the methyl group can modulate the function of the methyl-accepting species. These reactions are important in protecting organisms from environmental stresses and from the accumulation of spontaneous damage in aging cells. We will also develop methods to identify new types of methyltransferases that may catalyze previously unrecognized reactions in these pathways. We will determine the enzymology and functional roles of new members of the eucaryotic family of protein arginine methyltransferases (PRMTs). These enzymes alter the ability of the arginine residue to interact with RNA, DNA, and protein partners and have been shown to have roles in gene regulation, DNA repair, and intracellular signaling pathways. We will focus our work on mammalian systems, but will also use yeast and trypanosomes as model systems. We will pay special attention to the human PRMT7 protein that has been implicated in tumor formation and stem cell survival. Our overall goal is to establish the complete cast of characters of the enzymes that catalyze these modifications in nature so that their functions, especially in signaling and gene regulation in health and disease, can be fully understood. We will characterize new roles in intracellular signaling for the protein repair L-isoaspartyl/D-aspartyl methyltransferase. Here, we will utilize both mouse and worm (Caenorhabditis elegans) systems to explore the relationships between the accumulation of age-damaged proteins, their recognition by the protein repair methyltransferase, and the responses of the insulin/insulin-like signaling system to increase stress resistance and longevity. We will test several hypotheses to explain the physiological role of the linkage, including direct recognition of damaged proteins or methylated proteins by either the signaling pathway itself or a transcriptional system that upregulates one or more crucial members of the signaling pathway. We will determine the role of lysine protein methylation reactions in the translational apparatus, including ribosomal proteins and elongation factors. We will work in both yeast and mammalian cells to understand how the modifications of ribosomal proteins and eEF1A contribute to translational control and resistance to environmental toxins. Finally, we will use bioinformatic and biochemical approaches to search for and to characterize new types of methyltransferases in both yeast and humans. We are especially interested in identifying potential novel sites of methyltransferase inhibition associated with elevated plasma homocysteine levels in humans that have been linked to cardiovascular and neurological diseases.

描述（由申请人提供）：我们将研究生理功能如何通过甲基化反应来控制，重点是促进蛋白精氨酸，赖氨酸和异源质基因的修饰的酶。我们对参与信号转导和代谢调节途径的甲基转移酶特别感兴趣，在这些途径中，甲基的存在或不存在可以调节甲基受访物质的功能。这些反应对于保护生物免受环境应力和免受衰老细胞自发损害的积累而重要。我们还将开发方法来鉴定新型的甲基转移酶，这些甲基转移酶可能会催化这些途径中先前未识别的反应。我们将确定蛋白质精氨酸甲基转移酶（PRMTS）的新成员的新成员的酶学和功能作用。这些酶改变了精氨酸残基与RNA，DNA和蛋白质伴侣相互作用的能力，并已证明在基因调节，DNA修复和细胞内信号传导途径中具有作用。我们将把工作重点放在哺乳动物系统上，但也将使用酵母和锥虫作为模型系统。我们将特别注意与肿瘤形成和干细胞存活有关的人类PRMT7蛋白。我们的总体目标是建立酶的完整特征，这些酶在自然界中催化这些修饰，以便可以充分了解它们的功能，尤其是在健康和疾病中的信号传导和基因调节中。我们将在细胞内信号传导中表征蛋白质修复L-异源石/D-冬冬基甲基转移酶的新作用。在这里，我们将利用小鼠和蠕虫（Caenorhabditis秀丽隐杆线虫）系统来探索年龄损伤的蛋白质的积累，蛋白质修复甲基转移酶的识别以及胰岛素/胰岛素样信号系统的反应，以增加应激抗性和耐受性。我们将测试几种假设，以解释连锁的生理作用，包括通过信号通路本身或转录系统直接识别受损蛋白或甲基化蛋白质，该系统上调了信号传导途径的一个或多个至关重要的成员。我们将确定赖氨酸蛋白甲基化反应在翻译设备中的作用，包括核糖体蛋白和伸长因子。我们将在酵母和哺乳动物细胞中工作，以了解核糖体蛋白和EEF1A的修饰如何有助于转化和对环境毒素的抗性。最后，我们将使用生物信息学和生化方法来寻找并表征酵母和人类中新型的甲基转移酶。我们特别有兴趣确定与与心血管疾病和神经系统疾病有关的人类血浆同型半胱氨酸水平升高的甲基转移酶抑制作用。

项目成果

期刊论文数量（120）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein methylation at the surface and buried deep: thinking outside the histone box.

DOI：
10.1016/j.tibs.2013.02.004
发表时间：
2013-05
期刊：
TRENDS IN BIOCHEMICAL SCIENCES
影响因子：
13.8
作者：
Clarke, Steven G.
通讯作者：
Clarke, Steven G.

The ribosome: A hot spot for the identification of new types of protein methyltransferases

DOI：
10.1074/jbc.aw118.003235
发表时间：
2018-07-06
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Clarke, Steven G.
通讯作者：
Clarke, Steven G.

Adenine ribo- and deoxyribonucleotide metabolism in human erythrocytes, B- and T-lymphocyte cell lines, and monocyte-macrophages.

人红细胞、B 淋巴细胞和 T 淋巴细胞系以及单核巨噬细胞中的腺嘌呤核糖核苷酸和脱氧核糖核苷酸代谢。

DOI：
10.1073/pnas.82.19.6682
发表时间：
1985
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Valentine,WN;Paglia,DE;Clarke,S;Morimoto,BH;Nakatani,M;Brockway,R
通讯作者：
Brockway,R

Mechanistic studies on transcriptional coactivator protein arginine methyltransferase 1.