Uncovering novel players in nucleolar organization and function

项目总结 核仁是最大的无膜细胞器之一，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 细胞的蛋白质合成率和增殖能力。开创性研究表明，核仁增加 大小和数目是许多癌症的共同特征，核仁缺陷与 神经退行性疾病，包括阿尔茨海默氏症和帕金森氏症。然而，基本的 关于控制动态组装和分子机制的分子参与者和机制的信息仍然缺乏 核仁在健康和疾病中的活性。 我们鉴定了一种名为ZNF692的新的核仁蛋白，它是维持核仁完整性和 活动。击倒ZNF692导致核仁环状形态异常，并受损 蛋白质合成。我们的初步结果表明，ZNF692与多个核仁蛋白相互作用， 包括NPM1，以及rRNA加工和核糖体组装因子。我们的假设是ZNF692 通过同时招募前-rRNA、核糖体在核仁中组装核糖体生物发生中心 蛋白质和核糖体生物发生因子。我们将定义ZNF692调控的分子机制 核糖体生产(目标1)。我们将定义ZNF692调控核仁完整性和活性的结构域 (目标2)。然后，我们将确定ZNF692如何调控核仁组装和动力学(目标3)。我们的工作 有可能提供有关核仁活动的机制和关键调控因素的基本数据 可能成为开发改变病变细胞中核仁活性的新方法的基础。

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.