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.

项目概要 tRNA 修饰酶中的许多遗传变异与破坏性的神经发育和神经系统疾病。然而，分子这些病理的机制尚不清楚。为什么会产生扰动许多不同的 tRNA 修饰酶，因此，各种化学物质发生变化它们催化的改变似乎对大脑的影响比对其他器官的影响更大？到为了解决这个问题，我们的实验室试图阐明 tRNA 的分子和细胞作用修饰酶在人类健康和疾病中的作用。最近我们发现了一本小说 tRNA 合成酶样模拟物 DALRD3，是特定化学修饰所必需的人类 tRNA 的一个子集中。我们的初步结果表明 DALRD3 依赖性修饰影响 tRNA 构象稳定性和功能。值得注意的是，我们还鉴定出 DALRD3 基因中的常染色体隐性变异，该变异会导致功能和神经系统疾病癫痫性脑病。基于这些研究结果表明，DALRD3 介导的修饰在正确的特定 tRNA 的功能对于神经发育过程中的蛋白质合成很重要。在我们的第一个目标，我们将定义 tRNA 识别和修饰的要求依赖于 DALRD3 及其同源 tRNA 底物。为了我们的第二个目标，我们将测量 DALRD3 依赖性修饰对 tRNA 结构和功能的影响。在我们的最终目标中，我们将确定 DALRD3 依赖性 tRNA 修饰对通过核糖体分析在大脑中进行全局蛋白质翻译。总共，建议研究将对理解 tRNA 修饰如何影响影响正常的神经发育。尽管 DALRD3 在 tRNA 中是一个意想不到的参与者修改后，我们现在有了一个新的目标来探索个体的潜在治疗方法患有与 tRNA 生物学相关的癫痫性脑病。