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.

项目总结： 密码子的使用是每个基因和每个基因组的一个特定特征，并影响每个有机体的适合性。在……里面 遗传密码的简并性，蛋白质可以用多种方式编码，使用不同的同义词集合 密码子，在翻译速度或质量上不一样。同义词之间的每个密码子选择使 对tRNA与相匹配的反密码子的供应的需求。密码子-反密码子配对的性质 相互作用不仅由密码子的trna水平决定，还由表观遗传学决定。 转录后合成的tRNA的修饰。虽然大多数研究都集中在 TRNA的丰度作为密码子使用和细胞适合性的决定因素，对转录后的了解较少 修改。在过去的5年里，我的实验室一直专注于鸟嘌呤37位的N1-甲基化 在tRNAs中合成m1G37，这是蛋白质合成过程中维持阅读框架所必需的。损失 M1G37-tRNAs的突变导致核糖体+1移位的积累，导致蛋白质的提前终止 合成并最终导致细胞死亡。我们工作的一个关键发现是，虽然翻译需要m1G37 Pro的所有四个密码子，对于CC[C/U]密码子的翻译是必不可少的。因为Pro是独一无二的 氨基酸参与蛋白质合成，这一发现提供了有趣和重要的新生物学，其中m1G37- TRNA提供了一种全球机制来控制CC[C/U]富含基因的表达。在……的下一个前沿 研究中，我们将以CC[CU]依赖于m1G37的差异翻译为模型来阐明 TRNA的供需比控制细胞适合性的原则。我们将从分析 作为全基因组蛋白质合成报告的大肠杆菌的平衡生长。我们将测试的预测能力 阐明了测定人类蛋白质组的原理。我们还将讨论m1G的作用 甲基化，当被放置在致病线粒体tRNA(mt-tRNA)的第9位时，在 线粒体紊乱。通过探索我们拥有的独特方法和概念框架 ，我们将解决该领域的这些关键差距，并促进我们对密码子使用的理解 人类的健康和疾病。