Mechanisms and Regulation of Nuclear mRNA Export

项目摘要 mRNA从细胞核到细胞质的输出是真核基因表达的重要步骤。作为 mRNA是合成的，它被加工并与无数蛋白质包装成核糖核酸蛋白。 颗粒（mRNP）。我们的研究重点是确定mRNP蛋白的具体变化 这一过程被称为mRNP重塑，其驱动mRNA核输出的过程。的重要一步 其中mRNP经历广泛的重塑是形成有出口能力的mRNP。这是 由进化上保守的TREX（转录/输出）复合体介导，该复合体招募转运- 通过其ATP酶亚基Sub 2的作用将特异性蛋白质结合到核mRNP上。我们最近的发现 Sub 2激活机制的研究为定义分子事件的级联反应铺平了道路 从而产生具有出口能力的mRNP。总的来说，我在范德比尔特的实验室结合了结构的力量 生物学，生物化学，遗传学和细胞生物学，以阐明核mRNP重塑过程， 重点放在两个方面。首先，我们将确定事件的顺序和机制， 用于出口的mRNP。这包括表征核mRNP中关键参与者的机制 核mRNP重塑和前mRNA之间的分子联系的鉴定 加工步骤。第二，我们将研究mRNA输出如何在生理和生理条件下改变， 病理条件。我们试图了解mRNA的输出是如何调节特定的生物学特性的， 过程以及该途径的失调如何导致人类发病机制，如病毒感染。 最终，这些研究产生的知识将为mRNA输出提供重要的见解。 该途径既具有基本的细胞生物学重要性，又与人类健康和疾病相关。

Project Summary Export of mRNAs from the nucleus to the cytoplasm is an essential step in eukaryotic gene expression. As mRNA is synthesized, it is processed and packaged with a myriad of proteins to form ribonulceoprotein particles (mRNPs). Our research focuses on determining the specific changes in mRNP protein composition, referred to as mRNP remodeling, that drive the process of mRNA nuclear export. A major step where mRNPs undergo extensive remodeling is the formation of export-competent mRNPs. This is mediated by the evolutionarily conserved TREX (TRanscription/EXport) complex, which recruits transport- specific proteins onto a nuclear mRNP through the actions of its ATPase subunit Sub2. Our recent discovery of the activation mechanism of Sub2 has primed the way toward defining the cascade of molecular events that lead to export-competent mRNPs. Broadly, my lab at Vanderbilt combines the power of structural biology, biochemistry, genetics, and cell biology to elucidate the nuclear mRNP remodeling process with the focus on two areas. First, we will determine the sequence and mechanism of events that prepare nuclear mRNP for export. This includes characterization of the mechanism of key players in nuclear mRNP remodeling and identification of the molecular links between nuclear mRNP remodeling and pre-mRNA processing steps. Second, we will investigate how mRNA export is altered in response to physiological and pathological conditions. We seek to understand how mRNA export is tuned to regulate specific biological processes and how dysregulation of this pathway contributes to human pathogenesis such as viral infection. Ultimately, the knowledge generated from these studies will provide vital insights into the mRNA export pathway that is both of fundamental cell biological importance and is relevant to human health and disease.