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。mRNA的调控 水平是转录速率和降解速率之间的良好平衡。转录控制 是有据可查的虽然mRNA周转的主要途径是 确定，解释不同的半衰期一直难以捉摸。我的实验室已经证明 最优性是对真核生物中mRNA稳定性有很大贡献的一般特征。密码子 最优性反映了核糖体破译61个基因中每一个的不成比例的速率。 密码子mRNA解码过程中tRNA选择的随机性表现在 密码子最优性，其中tRNA浓度/功能显著影响速率。 因此，密码子最优性最终由同源tRNA的相对普遍性来衡量， 其中当tRNA过量时，密码子被认为是“最佳的”，反之则是“非最佳的”， 当tRNA的限制性更大时。密码子最优性也由热力学决定 密码子/反密码子配对的稳定性。我们的主要进展是表明， 降解机构监测核糖体速度，并在 核糖体运动相对缓慢。在这个提议中，我们研究了mRNA如何 降解复合物检测核糖体移位率作为密码子最优性的函数。我们 将决定在核糖体犹豫时发生的精确分子事件。 此外，我们专注于生物学背景，其中密码子最优性通过以下两种途径进行调节： mRNA化学修饰和tRNA调节表达。最后是密码子的影响 最优性现在被认为是酵母中mRNA稳定性的主要决定因素， 发展因此，通过这个项目的工作揭示了一个中心和关键的原则， 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.