Understanding the interconnection between mRNA turnover and mRNA translation

摘要 信使核糖核酸(Messenger RNA，mRNA)的衰退是基因表达调控的关键步骤。mrna 真核生物的衰变是通过去除3‘聚(A)尾巴(去烯基化)进行的 去掉5‘帽(去帽)，然后用5’-3‘核酸外切酶消化破坏mRNA。 这种衰变过程与mrna的翻译密切相关，也是field的一个主要目标。 就是理解翻译如何与衰变相互作用来设定衰减率。我们的实验室已经制作了 重要发现密码子最佳性是衰减率的关键决定因素转录组- 很宽。此外，我们还鉴定了fi死盒蛋白dhh1是检测到速度减慢的传感器。 与非最佳密码子相关的翻译延伸，并将这些消息定向到 砍头和降级。鉴于DHH1的这一新功能，这项建议旨在 了解DHH1感觉减慢翻译延伸和传递的机制 把这些信息传给拆解综合体。fi的第一个目标是了解DHH1如何 与核糖体相互作用以感觉延缓的伸长。第二个目标是DHH1如何 将减慢的伸长信号传输到去膜复合体。第三个目标是确定 死烯基化是如何使mRNA对DHH1敏感的。总而言之，这些目标将告诉DHH1 功能，从而提供对广泛的基因表达事件的洞察。

Abstract Messenger RNA (mRNA) decay is a critical step in the regulation of gene expression. mRNA decay in eukaryotes proceeds by removal of the 3' poly(A) tail (deadenylation) followed by removal of the 5' cap (decapping) then destruction of mRNA by 5' - 3' exonuclease digestion. This process of decay is intimately connected to mRNA translation, and a major goal of the field is to understand how translation interacts with decay to set decay rates. Our lab has made the important discovery that codon optimality is a critical determinant of decay rates transcriptome- wide. Further, we have identified the DEAD-box protein DHH1 as the sensor that detects slowed translation elongation associated with non-optimal codons and directs these messages to decapping and degradation. In light of this novel function for DHH1, this proposal seeks to understand the mechanism by which DHH1 senses slowed translation elongation and transmits this information to the decapping complex. The first aim is designed to understand how DHH1 interacts with the ribosome to sense slowed elongation. The second aim focuses on how DHH1 transmits a slowed elongation signal to the decapping complex. The third aim is to determine how deadenylation sensitizes mRNA to DHH1. Together, these aims will inform how DHH1 functions, thus providing insight into a wide range of gene expression events.