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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：
10612472
负责人：
Dragony Fu
金额：
$ 40.34万
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/10612472
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 Modeling Modification Molecular Mouse Strains Mus Mutation Neurodevelopmental Disorder Neurons Nucleotides Pathogenicity Pathology Pathway interactions Play Process Proliferating 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 brain abnormalities cell type density forging human disease insight loss of function neurodevelopment novel protein folding proteostasis ribosome profiling spatiotemporal tRNA Methyltransferases translational impact

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.

项目总结