Mechanisms and Regulation of Nuclear mRNA Export

核 mRNA 输出的机制和调控

• 批准号: 10441264
• 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/10441264
• 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.

项目概要 将 mRNA 从细胞核输出到细胞质是真核基因表达的重要步骤。作为 mRNA被合成，经过加工并与无数蛋白质一起包装形成核糖核蛋白 颗粒（mRNP）。我们的研究重点是确定 mRNP 蛋白的具体变化 组成，称为 mRNA 重塑，驱动 mRNA 核输出过程。迈出重要一步 mRNP 经历广泛重塑的过程是形成具有输出能力的 mRNP。这是 由进化上保守的 TREX (TRanscription/EXport) 复合物介导，该复合物招募运输- 通过 ATP 酶亚基 Sub2 的作用，将特定蛋白质附着到核 mRNA 上。我们最近的发现 Sub2 激活机制的研究为定义分子事件级联奠定了基础 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阐明核 mRNA 重塑过程 重点关注两个领域。首先，我们将确定核准备事件的顺序和机制。 用于导出的 mRNP。这包括核 mRNP 关键参与者机制的表征 核 mRNA 重塑和前 mRNA 之间分子联系的重塑和鉴定 处理步骤。其次，我们将研究 mRNA 输出如何根据生理和心理变化而改变。 病理状况。我们试图了解 mRNA 输出如何调整以调节特定的生物 过程以及该途径的失调如何导致病毒感染等人类发病机制。 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。