Mechanisms and Regulation of Nuclear mRNA Export

核 mRNA 输出的机制和调控

• 批准号: 10201667
• 负责人: Yi Ren
• 金额: $ 39.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201667
• 关键词: ATP phosphohydrolase; Area; Biochemistry; Biological; Biological Process; Cell Nucleus; Cells; Cellular biology; Complex; Cytoplasm; Disease; Eukaryotic Cell; Event; Gene Expression; Genetic; Genetic Transcription; Health; Human; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Nuclear; Nuclear Export; Pathogenesis; Pathologic; Pathway interactions; Physiological; Process; Proteins; Regulation; Research; Translations; Viral; Virus Diseases; human disease; insight; mRNA Export; mRNA Precursor; messenger ribonucleoprotein; nervous system disorder; particle; recruit; response; structural biology

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.

项目摘要 从细胞核出口到细胞质是真核基因表达的重要步骤。作为 MRNA合成，用无数蛋白质进行加工和包装以形成核糖蛋白 颗粒（mRNP）。我们的研究重点是确定MRNP蛋白的特定变化 组成，称为MRNP重塑，可驱动mRNA核出口的过程。主要步骤 MRNP进行广泛的重塑的地方是形成了能力的MRNP。这是 由进化保守的Trex（转录/出口）复合物介导，该复合物招募了运输 特异性蛋白质通过其ATPase亚基子2的作用到核mRNP上。我们最近的发现 Sub2的激活机制已为定义分子事件的级联 这导致了能力的MRNP。从广义上讲，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 关注两个领域。首先，我们将确定准备核事件的序列和机制 MRNP出口。这包括表征核mRNP中主要参与者的机制 核mRNP重塑与前MRNA之间的分子联系的重塑和鉴定 处理步骤。其次，我们将研究如何根据生理和 病理状况。我们试图了解如何调整mRNA导出以调节特定的生物学 该途径的过程以及该途径的失调如何有助于人类的发病机理，例如病毒感染。 最终，这些研究产生的知识将为mRNA导出提供重要的见解 途径是基本细胞生物学重要性，并且与人类健康和疾病有关。