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.

项目概要智力障碍 (ID) 是一种普遍存在的神经发育障碍，影响超过百分之一的人世界各地的个人。最近的遗传学研究已将许多 ID 病例与基因变异联系起来。修饰RNA化学结构的蛋白质。然而，tRNA 的机制修饰酶对大脑发育的影响是个谜。在此，我们重点解读 tRNA 甲基转移酶 1 (TRMT1) 的生物学作用，一种重要的 tRNA 修饰酶对于人类神经发育。携带 TRMT1 突变的个体表现出认知缺陷、生长障碍早年发育迟缓和大脑异常。我们发现 TRMT1 修饰超过哺乳动物细胞中所有 tRNA 的一半，并且是某些 tRNA 稳定性所必需的。而且，人类细胞中 TRMT1 的缺失会导致增殖缺陷和相关通路的上调在蛋白质折叠中。为了了解 TRMT1 在神经发育中的功能，我们生成了一种新的 TRMT1 缺陷小鼠品系，表现出大脑和发育异常。基于这些发现，我们认为 TRMT1 催化的修饰在 tRNA 的生物合成和功能，以确保蛋白质合成的适当水平哺乳动物的生长和发育。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 稳定性中的作用的技术功能。在我们的第二个目标中，我们将使用核糖体分析方法来破译核糖体的作用 TRMT1 催化翻译中的 tRNA 修饰。对于我们的最终目标，我们将定义小鼠大脑发育中 TRMT1 的时空需求。总而言之，拟议的研究将在 RNA 修饰、蛋白质合成和神经发育。