tRNA in codon usage

密码子使用中的 tRNA

• 批准号: 10371216
• 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/10371216
• 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

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.

项目概要： 密码子使用是每个基因和每个基因组的特定特征，并影响每个生物体的适应性。在 由于遗传密码的简并性，蛋白质可以使用不同的同义词集合以多种方式编码。 密码子，其在速度或质量上不相等地翻译。同义词之间的每个密码子选择 需要提供具有匹配反密码子的tRNA。密码子-反密码子配对的质量 相互作用不仅由密码子的tRNA水平决定，而且还由表观遗传学决定。 对转录后合成的tRNA进行修饰。虽然大多数研究都集中在 大量的tRNA作为密码子使用和细胞适应性的决定因素，但对转录后水平的研究却知之甚少。 修改.在过去的5年里，我的实验室专注于37位鸟嘌呤的N1-甲基化， 在tRNA中合成m1 G37，这是蛋白质合成过程中维持阅读框所必需的。损失 m1 G37-tRNA的表达导致核糖体+1-移位的积累，导致蛋白质的提前终止 最终导致细胞死亡。我们的工作的一个关键发现是，虽然m1 G37是翻译所必需的， 所有四个密码子为脯氨酸（Pro），它是CC[C/U]密码子翻译所必需的。因为Pro是一个独特的 蛋白质合成中的氨基酸，这一发现提供了有趣和重要的新生物学，其中m1 G37- tRNA提供了控制CC[C/U]富集基因表达的全局机制。在下一个前沿领域， 研究中，我们将专注于CC[CU]的m1 G37依赖性差异翻译作为模型来阐明 这是tRNA的供需比例决定细胞适应性的原理。我们将首先分析 平衡生长E. coli作为全基因组蛋白质合成的报告基因。我们将测试 阐明了人类蛋白质组测定的原理。我们还将讨论m1 G的作用 甲基化，当位于致病性线粒体tRNA（mt-tRNA）的9位时，在 线粒体紊乱通过探索我们所拥有的独特的方法和概念框架， 我们将解决该领域的这些关键空白，并推进我们对密码子使用的理解， 人类健康和疾病。