Determining the influence of codon optimality on mRNA translation and decay

确定密码子最优性对 mRNA 翻译和衰变的影响

• 批准号: 9753278
• 负责人: Jeffery Coller
• 金额: $ 31.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753278
• 关键词: 3' Untranslated Regions; Accounting; Cells; Code; Codon Nucleotides; Collaborations; Cultured Cells; DNA; Data; Defect; Drosophila genus; Embryo; Engineering; Enzymes; Eukaryota; Expression Library; Failure; Gene Expression; Gene Expression Regulation; Genetic Code; Genetic Translation; Grant; Health; Human; In Vitro; Kinetics; Lead; Malignant Neoplasms; Mammalian Cell; Mammals; Measurement; Measures; Messenger RNA; Monitor; Neurologic; Output; Pathway interactions; Physiological; Play; Positioning Attribute; Post-Transcriptional Regulation; Proteins; RNA; RNA Decay; RNA Degradation; RNA Helicase; Reporter; Ribosomes; Role; Saccharomycetales; Series; Signal Transduction; System; Time; Transfer RNA; Translation Process; Translations; Universities; Work; Yeast Model System; Yeasts; base; fly; genetic information; genome-wide; in vivo; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mRNA decapping; malformation; mutant; reconstitution; ribosome profiling; transcriptome

Abstract Messenger RNA degradation represents a critical step in the regulation of gene expression. While the major pathways and enzymes catalyzing mRNA turnover have been identified, accounting for disparate half-lives has been elusive. Recently, we have discovered that codon optimality is a major feature that contributes greatly to mRNA stability. Codon optimality is a term to describe the fact that tRNA levels are not the same in the cell. Thus is it predicted that each of the 61 codons is read by the ribosome at a slightly different rate. Codons whose tRNA levels are high are termed optimal codons, while codons whose tRNA levels are low are termed non-optimal codons. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominantly non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, while the converse substitution significantly increases stability. Further, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. We suggest that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay. This work demonstrates that the degeneracy in the genetic code exists as a mechanism to finely tune levels of mRNAs, and ultimately, proteins through codon optimality. We will continue to investigate the influence of codon optimality on gene expression in this proposal.

抽象的 信使 RNA 降解是基因表达调控的关键一步。 虽然催化 mRNA 更新的主要途径和酶已被确定， 解释不同的半衰期一直难以捉摸。最近，我们发现密码子 最优性是对 mRNA 稳定性有很大贡献的一个主要特征。密码子最优性是 该术语描述了细胞中 tRNA 水平不同的事实。由此可见， 核糖体读取 61 个密码子的速度略有不同。密码子的 tRNA 水平高的密码子被称为最佳密码子，而 tRNA 水平低的密码子被称为最佳密码子。 称为非最佳密码子。全基因组 RNA 衰减分析揭示稳定的 mRNA 富含被指定为最佳的密码子，而不稳定的 mRNA 主要包含 非最佳密码子。用同义的非最佳密码子替换最佳密码子 导致 mRNA 急剧不稳定，而反向取代显着增加 稳定。此外，我们表明最佳密码子含量具有相似的稳定性 在编码具有协调生理功能的蛋白质的 mRNA 中观察到。我们建议 密码子最优性影响核糖体易位，连接翻译过程 伸长和衰减。这项工作表明遗传密码的简并性存在于 一种通过密码子优化微调 mRNA 水平并最终调节蛋白质水平的机制。 我们将继续研究密码子最优性对基因表达的影响 提议。