Understanding the interconnection between mRNA turnover and mRNA translation

摘要 信使RNA（mRNA）的降解是基因表达调控的关键步骤。mRNA 真核生物中的衰变通过去除3' poly（A）尾（去腺苷酸化），然后 除去5 ′帽（去帽），然后通过5 ′-3 ′核酸外切酶消化破坏mRNA。 这种衰变过程与mRNA翻译密切相关，也是该领域的一个主要目标。 是了解翻译如何与衰变相互作用以设定衰变率。我们的实验室已经制造出 密码子最优性是转录组衰变率的关键决定因素， 宽此外，我们已经确定了艾德的死亡盒蛋白DHH 1作为传感器，检测减缓 翻译延长与非最佳密码子，并指导这些信息， 开盖和降解。鉴于DHH 1的这种新功能，本提案旨在 了解DHH 1感觉减缓翻译延伸和传递的机制 将此信息发送到开盖综合体。第一个目的是了解DHH 1 与核糖体相互作用以感知缓慢的延伸。第二个目标是DHH 1 将减慢的伸长信号传递到去盖复合体。第三个目标是确定 去腺苷化如何使mRNA对DHH 1敏感。总之，这些目标将告知DHH 1 功能，从而提供了深入了解广泛的基因表达事件。

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.