Molecular functions of the TRMT1 tRNA modification enzyme

TRMT1 tRNA修饰酶的分子功能

基本信息

批准号：
10178481
负责人：
Dragony Fu
金额：
$ 45.73万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10178481
关键词：
Affect Age Aminoacylation Area Biogenesis Biological Brain Cell Count Cells Charge Chemical Structure Codon Nucleotides Cognitive deficits Complement Defect Development Developmental Delay Disorders Disease Ensure Enzymes Eukaryota Exhibits Foundations Genes Genetic study Goals Growth Growth and Development function Guanosine Health Human Impaired cognition Impairment Individual Intellectual functioning disability Knockout Mice Knowledge Link Mammalian Cell Measures Methylation Modeling Modification Molecular Mouse Strains Mus Mutation Neurodevelopmental Disorder Neurons Nucleotides Pathogenicity Pathology Pathway interactions Play Process Protein Biosynthesis Proteins RNA RNA Splicing Research Ribosomes Role System Technology Testing Tissues Transfer RNA Transfer RNA Aminoacylation Translations Tyrosine-Specific tRNA Up-Regulation Variant base brain abnormalities cell type density human disease insight loss of function neurodevelopment novel protein folding proteostasis ribosome profiling spatiotemporal tRNA Methyltransferases

项目摘要

PROJECT SUMMARY Intellectual disability (ID) is a prevalent neurodevelopmental disorder affecting more than 1 in 100 individuals worldwide. Recent genetic studies have linked numerous cases of ID to variants in proteins that modify the chemical structure of RNA. However, the mechanisms by which tRNA modification enzymes influence brain development are enigmatic. Here, we focus on deciphering the biological role of tRNA methyltransferase 1 (TRMT1), a tRNA modification enzyme important for human neurodevelopment. Individuals with TRMT1 mutations exhibit cognitive deficits, growth delay and brain abnormalities early in age. We have discovered that TRMT1 modifies more than half of all tRNAs in mammalian cells and is required for the stability of certain tRNAs. Moreover, loss of TRMT1 in human cells causes proliferation defects and up-regulation of pathways involved in protein folding. To understand the function of TRMT1 in neurodevelopment, we have generated a novel TRMT1-deficient mouse strain which exhibits brain and developmental abnormalities. Based upon these findings, we propose that TRMT1-catalyzed modifications play a critical role in the biogenesis and function of tRNAs to ensure proper levels of protein synthesis during mammalian growth and development. In our first Aim, we will use new tRNA sequencing technologies to determine the role of TRMT1-catalyzed modifications in tRNA stability and function. In our second Aim, we will use ribosome profiling approaches to decipher the role of TRMT1-catalyzed tRNA modification in translation. For our final Aim, we will define the spatiotemporal requirement for TRMT1 in mouse brain development. Altogether, the proposed research will forge new connections between RNA modification, protein synthesis and neurodevelopment.

项目摘要智力残疾（ID）是一种普遍的神经发育障碍，影响超过100分之一全球个人。最近的遗传研究已将众多ID病例与变体联系在一起改变RNA的化学结构的蛋白质。但是，tRNA的机制修饰酶会影响大脑发育是神秘的。在这里，我们专注于解密 TRNA甲基转移酶1（TRMT1）的生物学作用，TRNA修饰酶很重要用于人类神经发育。具有TRMT1突变的个体表现出认知缺陷，生长延迟和大脑异常早年。我们发现TRMT1比哺乳动物细胞中所有TRNA的一半，是某些TRNA的稳定性所必需的。而且，人类细胞中TRMT1的丧失会导致增殖缺陷和涉及途径的上调在蛋白质折叠中。要了解TRMT1在神经发育中的功能，我们已经生成了一种新型的TRMT1缺陷小鼠菌株，表现出脑和发育异常。根据这些发现，我们建议TRMT1催化的修饰在 TRNA的生物发生和功能，以确保在哺乳动物的生长和发展。在我们的第一个目标中，我们将使用新的trna测序确定TRMT1催化修饰在tRNA稳定性和功能。在第二个目标中，我们将使用核糖体分析方法来破译 TRMT1催化的TRNA修饰在翻译中。为了我们的最终目标，我们将定义小鼠脑发育中TRMT1的时空需求。总共提议研究将在RNA修饰，蛋白质合成和神经发育。