Determining the influence of codon optimality on mRNA translation and decay

摘要 信使RNA降解是基因表达调控的关键步骤。 虽然催化mRNA周转的主要途径和酶已经被鉴定， 对不同半衰期的解释一直是难以捉摸的。最近，我们发现， 最优性是极大地有助于mRNA稳定性的主要特征。密码子最优性是 术语描述细胞中tRNA水平不相同的事实。因此，据预测， 61个密码子中的每一个被核糖体以略微不同的速率读取。密码子， 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mRNA 富含指定的最佳密码子，而不稳定的mRNA主要含有 非最佳密码子。用同义的非最佳密码子替换最佳密码子 导致显著的mRNA不稳定，而匡威的取代显著增加 稳定此外，我们发现，最佳密码子含量占类似的稳定性 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 密码子优化影响核糖体转位，连接翻译过程 伸长和衰变。这项工作表明，遗传密码中的简并性存在， 这是一种通过密码子优化来微调mRNA水平并最终微调蛋白质水平的机制。 我们将继续研究密码子优化对基因表达的影响， 提议

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.