tRNA in codon usage

密码子使用中的 tRNA

• 批准号: 10576809
• 负责人: Ya-Ming Hou
• 金额: $ 54.6万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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/10576809
• 关键词: Address; Amino Acids; Anticodon; Biology; Cell Death; Cells; Code; Codon Nucleotides; Development; Disease; Epigenetic Process; Escherichia coli; Genes; Genetic Code; 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; Testing; Transfer RNA; Translations; Work; fitness; frontier; genome-wide; posttranscriptional; premature

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，而且还通过表观遗传来确定 修改转录后合成的tRNA。虽然大多数研究都集中在 丰度作为密码子使用和细胞健身的决定因素，对转录后的了解较少 修改。在过去的5年中，我的实验室专注于鸟嘌呤的N1-甲基化，位于37位的位置 在TRNA中合成M1G37，这是蛋白质合成过程中读取框架维持所必需的。损失 M1G37-TRNA的核体导致核糖体 +1-割的积累，从而导致蛋白质的成熟终止 合成并最终导致细胞死亡。我们工作的一个关键发现是，虽然M1G37是需要翻译的 脯氨酸（Pro）的所有四个密码子，对于CC [C/U]密码子的翻译至关重要。因为Pro是一个独特的 氨基酸在蛋白质合成中，这一发现提供了有趣而重要的新生物学，其中M1G37-- TRNA提供了控制CC [C/U]富集基因表达的全局机制。在下一个边界 研究，我们将重点介绍CC [CU]的M1G37依赖性差分翻译，以阐明该模型 TRNA的供求比控制细胞健身的原则。我们将从分析 大肠杆菌作为全基因组蛋白质合成的记者的平衡生长。我们将测试 确定人蛋白质组的阐明原则。我们还将解决M1G的角色 将甲基化放置在致病线粒体tRNA（mt-tRNA）的位置时， 线粒体疾病。通过探索我们拥有的独特方法和概念框架 开发，我们将解决该领域的这些关键差距，并提高我们对密码子使用情况的理解 人类健康和疾病。