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Mechanism and functions of DALRD3-dependent tRNA modification

DALRD3依赖性tRNA修饰的机制和功能

基本信息

批准号：
10706953
负责人：
Dragony Fu
金额：
$ 30.8万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706953
关键词：
Affect Alleles Amino Acyl-tRNA Synthetases Aminoacylation Anticodon Arginine Binding Biological Biology Brain Brain Diseases Cells Chemicals Codon Nucleotides Complex Development Developmental Delay Disorders Disease Elements Ensure Enzymes Epilepsy Exhibits Foundations Genes Goals Health Human Individual Knock-out Link Mammalian Cell Measures Mediating Messenger RNA Methylation Methyltransferase Modification Molecular Molecular Biology Molecular Conformation Monitor Mouse Strains Multienzyme Complexes Mus Neurodevelopmental Disorder Neurologic Organ Pathogenicity Pathology Patients Physiological Play Protein Biosynthesis Proteins RNA Biochemistry RNA Conformation RNA Folding RNA Sequences RNA Stability RNA methylation Reporter Research Ribosomal Interaction Ribosomes Role Structure Testing Therapeutic Transfer RNA Translations Variant autosome brain tissue epileptic encephalopathies genetic variant insight loss of function nervous system disorder neurodevelopment novel recruit ribosome profiling

项目摘要

PROJECT SUMMARY Numerous genetic variants in tRNA modification enzymes have been linked to devastating neurodevelopmental and neurological disorders. However, the molecular mechanisms underpinning these pathologies are unknown. Why is it that perturbations to many different tRNA modification enzymes and thus, changes to the various chemical modifications they catalyze, seem to affect the brain more so than other organs? To resolve this question, our lab seeks to elucidate the molecular and cellular roles of tRNA modification enzymes in human health and disease. We have recently uncovered a novel tRNA synthetase-like mimic, DALRD3, that is required for a specific chemical modification in a subset of human tRNAs. Our preliminary results suggest that the DALRD3-dependent modification impacts tRNA conformational stability and function. Notably, we have also identified an autosomal-recessive variant in the DALRD3 gene that causes loss of function and the neurological disorder epileptic encephalopathy. Based upon these findings, we propose that DALRD3-mediated modification plays a critical role in the proper function of specific tRNAs important for protein synthesis during neurodevelopment. In our first Aim, we will define the requirements for tRNA recognition and modification dependent in DALRD3 and its cognate tRNA substrates. For our second Aim, we will measure the impact of DALRD3-dependent modification on tRNA structure and function. In our final Aim, we will determine the role of DALRD3-dependent tRNA modification on global protein translation in the brain through ribosome profiling. In total, the proposed research will have broad implications in understanding how tRNA modifications can impact proper neurodevelopment. Although DALRD3 was an unexpected player in tRNA modification, we now have a new target to explore potential therapeutics for individuals suffering from epileptic encephalopathies linked to tRNA biology.

项目总结