Determining the influence of codon optimality on mRNA translation and decay

摘要 信使RNA的降解是基因表达调控的关键一步。 虽然已经确定了催化mRNA周转的主要途径和酶， 如何解释不同的半衰期一直难以捉摸。最近，我们发现密码子 最佳性是对信使核糖核酸稳定性有很大贡献的一个主要特征。密码子最佳性是一个 这个术语用来描述细胞中tRNA水平不同的事实。因此，据预测， 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衰变分析显示稳定的mRNAs 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、非最佳密码子替换最佳密码子 导致显著的mRNA失稳，而反向替代显著增加 稳定性。此外，我们还证明了最优密码子含量可以解释相似的稳定性 在编码具有协调生理功能的蛋白质的mRNAs中观察到。我们建议 密码子优化影响核糖体易位，连接翻译过程 伸长和腐烂。这项工作证明了遗传密码中的简并性存在于 一种通过密码子最优化来微调mRNAs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佳性对基因表达的影响。 求婚。

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.