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.

项目概要： 密码子的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组以多种方式编码 密码子的翻译速度或质量并不相同。同义词之间的每个密码子选择都使得 对提供具有匹配反密码子的 tRNA 的需求。密码子-反密码子配对的质量 相互作用不仅取决于密码子 tRNA 的水平，还取决于表观遗传 对转录后合成的 tRNA 进行修饰。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应性的决定因素，但对转录后的了解较少 修改。在过去的 5 年里，我的实验室重点研究了 37 位鸟嘌呤的 N1-甲基化， 在 tRNA 中合成 m1G37，这是蛋白质合成过程中维持阅读框所必需的。损失 m1G37-tRNA 的增加导致核糖体 +1 位移的积累，导致蛋白质过早终止 合成并最终导致细胞死亡。我们工作的一个重要发现是，虽然翻译需要 m1G37 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 是独一无二的 蛋白质合成中的氨基酸，这一发现提供了有趣且重要的新生物学，其中 m1G37- tRNA 提供了控制 CC[C/U] 富集基因表达的全局机制。在下一个前沿 研究中，我们将重点关注 CC[CU] 依赖于 m1G37 的差异翻译作为模型来阐明 tRNA 供需比控制细胞适应性的原则。我们将从分析开始 大肠杆菌作为全基因组蛋白质合成的报告基因的平衡生长。我们将测试预测能力 阐明了确定人类蛋白质组的原理。我们还将讨论 m1G 的作用 当甲基化位于致病性线粒体 tRNA (mt-tRNA) 的第 9 位时， 线粒体疾病。通过探索我们拥有的独特方法和概念框架 开发完成后，我们将解决该领域的这些关键差距，并增进我们对密码子使用的理解 人类健康和疾病。