Uncovering novel players in nucleolar organization and function

发现核仁组织和功能中的新参与者

• 批准号: 10621238
• 负责人: Maralice Conacci-Sorrell
• 金额: $ 32.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621238
• 关键词: Alzheimer' s Disease; Architecture; Binding; Biogenesis; Cell Cycle; Cell Nucleolus; Cells; Complex; Data; Defect; Development; Disease; Experimental Designs; Fingers; Generations; Genetic Transcription; Health; Immunoprecipitation; In Vitro; Knock-out; Maintenance; Malignant Neoplasms; Mammalian Cell; Measures; Membrane; Molecular; Morphology; NPM1 gene; Names; Neurodegenerative Disorders; Nucleolar Proteins; Organelles; Parkinson Disease; Pathologist; Pathway interactions; Point Mutation; Production; Property; Protein Biosynthesis; Proteins; RNA; RNA Processing; Regulation; Research; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Seminal; Signal Transduction; Solid Neoplasm; Specific qualifier value; Structure; Testing; Translations; Work; Yeasts; Zinc Fingers; cell growth; human disease; in vivo; knock-down; novel; novel strategies; overexpression; recruit; self organization

PROJECT SUMMARY The nucleolus is one of the largest membraneless cellular organelles, responsible for ribosomal RNA (rRNA) transcription, rRNA processing, and ribosome assembly. Nucleolar size and number are often correlated with protein synthesis rate and proliferative capacity of a cell. Seminal studies have shown that increased nucleolar size and number are common features of many cancers and that nucleolar defects are associated with neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Nevertheless, fundamental information is still lacking on the molecular players and mechanism that control the dynamic assembly and activity of the nucleolus in health and disease. We identified a novel nucleolar protein named ZNF692 that is necessary to maintain nucleolar integrity and activity. Knocking down ZNF692 resulted in abnormal ring-like nucleolar morphology, as well as compromised protein synthesis. Our preliminary results indicate that ZNF692 interacts with multiple nucleolar proteins, including NPM1, as well as rRNA processing and ribosome assembly factors. Our hypothesis is that ZNF692 assembles a hub for ribosome biogenesis in the nucleolus by simultaneously recruiting pre-rRNA, ribosomal proteins, and ribosome biogenesis factors. We will define the molecular mechanism regulated by ZNF692 in ribosome production (Aim 1). We will define the domains of ZNF692 that regulate nucleolar integrity and activity (Aim 2). We will then determine how ZNF692 may regulate nucleolar assembly and dynamics (Aim 3). Our work has the potential to provide fundamental data on the mechanisms and key regulators of nucleolar activity and could become the basis for the development of novel approaches to alter nucleolar activity in diseased cells.

项目摘要 核仁是最大的无膜细胞细胞器之一，负责核糖体RNA（rRNA） 转录，rRNA加工和核糖体组装。核仁的大小和数量通常与 蛋白质的合成速率和细胞的增殖能力。开创性研究表明核仁增加 大小和数量是许多癌症的常见特征，核缺陷与 神经退行性疾病，包括阿尔茨海默氏症和帕金森氏病。然而，基本 仍然缺乏控制动态组装的分子参与者和机制的信息 核仁在健康和疾病中的活性。 我们确定了一种名为Znf692的新型核蛋白，这是维持核完整性和 活动。击倒Znf692导致了异常的环形核形态，并妥协 蛋白质合成。我们的初步结果表明Znf692与多种核仁蛋白相互作用， 包括NPM1，以及rRNA加工和核糖体组装因子。我们的假设是Znf692 通过简单地募集核糖体，核糖体的核糖体组装核糖体生物发生的枢纽 蛋白质和核糖体生物发生因子。我们将定义由Znf692调节的分子机制 核糖体产生（AIM 1）。我们将定义调节核完整性和活性的ZnF692领域 （目标2）。然后，我们将确定ZNF692如何调节核装配和动力学（AIM 3）。我们的工作 有潜力提供有关核活动机制和关键调节因子的基本数据和 可以成为开发新方法改变患病细胞中核活动的基础。