tRNA in codon usage

密码子使用中的 tRNA

基本信息

批准号：
10581912
负责人：
Ya-Ming Hou
金额：
$ 21.33万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581912
关键词：
Address Amino Acids Anticodon Biology Cell Death Cells Code Codon Nucleotides Development Disease Epigenetic Process Escherichia coli Genes Genetic Code Genetic Transcription Genome Growth Guanine Health Human Maintenance Methodology Methylation Mitochondria Mitochondrial Diseases Modeling Modification Organism Pathogenicity Pattern Positioning Attribute Proline Protein Biosynthesis Proteins Proteome Reading Frames Reporter Research Ribosomes Role Speed Transfer RNA Translations Work fitness frontier genome-wide predictive test premature

Address Amino Acids Anticodon Biology Cell Death Cells Code Codon Nucleotides Development Disease Epigenetic Process Escherichia coli Genes Genetic Code Genetic Transcription Genome Growth Guanine Health Human Maintenance Methodology Methylation Mitochondria Mitochondrial Diseases Modeling Modification Organism Pathogenicity Pattern Positioning Attribute Proline Protein Biosynthesis Proteins Proteome Reading Frames Reporter Research Ribosomes Role Speed Transfer RNA Translations Work fitness frontier genome-wide predictive test premature

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项目摘要

PROJECT SUMMARY: Codon usage is a specific feature of each gene and each genome and impacts the fitness of each organism. In the degeneracy of the genetic code, proteins can be coded in multiple ways using different sets of synonymous codons, which are not translated equally in speed or quality. Each codon choice between the synonyms makes a demand for the supply of the tRNA with the matching anticodon. The quality of a codon-anticodon pairing interaction is determined not only by the level of the tRNA for the codon, but also by the epigenetic modifications to the tRNA that are synthesized post-transcriptionally. While most studies have focused on the abundance of tRNA as a determinant of codon usage and cell fitness, less is known about post-transcriptional modifications. In the past 5 years, my lab has focused on the N1-methylation of the guanine at position 37 that synthesizes m1G37 in tRNAs, which is required for reading-frame maintenance during protein synthesis. Loss of m1G37- tRNAs leads to accumulation of ribosomal +1-shifts, resulting in pre-mature termination of protein synthesis and ultimately cell death. A key finding of our work is that, while m1G37 is required for translation of all four codons for proline (Pro), it is essential for translation of CC[C/U] codons. Because Pro is a unique amino acid in protein synthesis, this finding offers interesting and important new biology, in which m1G37-tRNAs provide a global mechanism to control the expression of CC[C/U]-enriched genes. In the next frontier of research, we will focus on the m1G37-dependent differential translation of CC[CU] as a model to elucidate the principles by which the supply-to-demand ratio of tRNAs governs cell fitness. We will start by analysis of the balanced growth of E. coli as a reporter for genome-wide protein synthesis. We will test the predictive power of the elucidated principles in determining the human proteome. We will also address the role of m1G methylation, when placed at position 9 of a pathogenic mitochondrial tRNA (mt-tRNA), in the development of the mitochondrial disorder. By exploring the unique methodologies and conceptual frameworks that we have developed, we will address these key gaps in the field and advance our understanding of codon usage in human health and disease.

项目摘要：密码子的使用是每个基因和每个基因组的特定特征，并且会影响每个生物体的适应性。在遗传密码的退化，可以使用不同的同义词以多种方式对蛋白质进行编码密码子，速度或质量不平等地翻译。同义词之间的每个密码子选择用匹配的反密码子供应tRNA的需求。密码子 - 古代配对的质量相互作用不仅取决于密码子的tRNA水平，而且还取决于表观遗传修饰到转录后合成的tRNA。虽然大多数研究都集中于丰富 tRNA是密码子使用和细胞适应性的决定因素，对转录后修饰知之甚少。在过去的5年中，我的实验室集中于鸟嘌呤的N1-甲基化，位于37位的位置 M1G37在TRNA中，这是蛋白质合成过程中阅读框架维持所需的。 M1G37-的损失 TRNA导致核糖体 +1割的积累，导致蛋白质合成的成熟终止和最终的细胞死亡。我们工作的关键发现是，虽然M1G37是翻译所有四个密码子所必需的对于脯氨酸（Pro），对于CC [C/U]密码子的翻译至关重要。因为Pro是蛋白质中独特的氨基酸综合，这一发现提供了有趣而重要的新生物学，其中M1G37-TRNA提供了全球控制CC [C/U]富集基因的表达的机制。在下一个研究领域，我们将集中精力在CC [CU]的M1G37依赖性差分翻译上，作为阐明原理的模型 TRNA的供需比率控制细胞健身。我们将从分析大肠杆菌的平衡生长开始作为全基因组蛋白质合成的记者。我们将测试阐明原则的预测能力确定人类蛋白质组。当放置在第9位时，我们还将解决M1G甲基化的作用线粒体疾病发展中的致病线粒体tRNA（MT-tRNA）。通过探索我们开发的独特方法和概念框架，我们将解决这些关键差距在现场并提高我们对人类健康和疾病中密码子使用情况的理解。