Understanding the relationship between codon optimality and mRNA stability

项目摘要 信使RNA将遗传信息从DNA传递到蛋白质。基因的转录调控 水平是转录速率和降解速率之间的一个很好的平衡。转录调控 都得到了很好的记录和研究。尽管信使核糖核酸转换的主要途径是 尽管已经确定，但对不同的半衰期的解释一直难以捉摸。我的实验室证明了密码子 优化性是真核生物中对信使核糖核酸稳定性有很大贡献的一个普遍特征。密码子 最佳性反映了核糖体破译61个核糖体的不成比例的速度 密码子。在mRNA解码过程中，tRNA选择的随机性体现在 密码子最佳性，其中tRNA浓度/功能显著影响速率。 因此，密码子最佳性最终由同源tRNA的相对流行率来衡量， 其中当tRNA过多时，密码子被认为是最佳的，反之则被认为是非最佳的 当tRNA更具限制性的时候。密码子的最佳性也由热力学决定。 密码子/反密码子配对的稳定性。我们的主要进展是表明， 降解机械监测核糖体速度，并在以下情况下响应降解消息 核糖体运动相对较慢。在这个方案中，我们研究了mRNA是如何 降解复合体感觉核糖体转移率是密码子最佳性的函数。我们 将确定核糖体犹豫不决时发生的确切分子事件。 此外，我们将重点放在密码子最佳性通过以下两个途径调节的生物学背景上 MRNA化学修饰和tRNA调控表达。最后，密码子的影响 最佳性现在被认为是酵母和早期mrna稳定性的主要决定因素。 发展。因此，通过该项目的工作揭示了 对基因表达调控有广泛贡献的生物学。

Project Summary Messenger RNA transmits genetic information from DNA to protein. The regulation of mRNA levels is a fine balance between transcription rate and degradation rate. Transcriptional control is well documented and studied. Although the major pathways in mRNA turnover have been identified, accounting for disparate half-lives has been elusive. My lab has shown that codon optimality is a general feature that contributes greatly to mRNA stability in eukaryotes. Codon optimality reflects the disproportionate rate by which the ribosome deciphers each of the 61 codons. The randomness of tRNA selection during the mRNA decoding process manifests in codon optimality wherein tRNA concentrations/functionality dramatically influence rate. Accordingly, codon optimality is ultimately gauged by the relative prevalence of cognate tRNAs, wherein a codon is deemed `optimal' when tRNAs are in excess and conversely `non-optimal' when tRNAs are more limiting. Codon optimality is also determined by the thermodynamic stability of codon/anticodon pairing. Our major advance has been to show that the mRNA degradation machinery monitors ribosome speed and responds to degrade message when ribosome movement is relatively slow. In this proposal, we investigate how the mRNA degradation complex senses ribosome translocation rate as a function of codon optimality. We will determine the precise molecular events that occur in response to ribosome hesitations. Moreover, we focus on biological context where codon optimality is regulated both through mRNA chemical modification and tRNA regulated expression. Lastly the influence of codon optimality is now seen to be the major determinant of mRNA stability in yeast and in early development. Thus work through this project has uncovered a central and critical principle in biology that contributes broadly to gene expression regulation.