Mechanisms and Regulation of Nuclear mRNA Export

项目摘要 将mRNAs从细胞核输出到细胞质是真核基因表达的重要步骤。AS MRNA被合成，它被加工并与无数的蛋白质包装形成核糖核酸蛋白 粒子(MRNP)。我们的研究重点是确定mRNP蛋白的具体变化 组成，被称为mRNP重塑，驱动着mRNA核输出的过程。重要的一步 在mRNP经历广泛重塑的地方，是形成具有出口能力的mRNPs。这是 由进化上保守的TREX(转录/输出)复合体介导，它招募运输- 通过其ATPase亚基Sub2的作用将特定的蛋白质结合到核内的mRNP上。我们的最新发现 对Sub2的激活机制的研究为定义分子事件的级联奠定了基础 这导致了具有出口能力的核反应堆。总的来说，我在范德比尔特的实验室结合了结构性技术的力量 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，我们将确定准备核的事件的顺序和机制 用于出口的MRNP。这包括描述核mrnp中关键角色的机制。 核内mRNP重塑与前信使核糖核酸分子连接的重塑与鉴定 处理步骤。其次，我们将研究mrna输出是如何改变的，以响应生理和 病理情况。我们试图了解信使核糖核酸的输出是如何被调节以调节特定的生物的。 以及这一途径的失调如何促进人类的发病，如病毒感染。 最终，这些研究产生的知识将为信使核糖核酸的输出提供重要的见解。 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的途径。

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.