Structure and Regulation of snoRNP Interaction with rRNA

描述(申请人提供)：核糖体生物发生是一个基本的细胞过程，必须满足正常细胞生长和应激反应的要求。核糖体生物发生的基础是核糖体RNA的合成。在这个过程中，核糖体RNA被小核仁核糖核蛋白颗粒(SnoRNPs)捕获、化学修饰、切割和释放。多年来，我实验室的研究表明了一种新兴的原理，即snoRNPs捕获rRNA的单一行为包括同时发生的多个协调事件，并在活性部位远端的位置进行催化。多组分但易处理的H/ACA snoRNP为详细研究这些相互作用提供了一个原型系统。我们的目标是建立一个从最初的对接到化学反应结束的snoRNPs捕获和释放核糖体RNA的机械观点。拟议的研究还将提供对RNA-蛋白质复合酶的原子细节的一般了解。癌细胞表现为核糖体合成增加。识别抑制或促进核糖体合成的信号将可能揭示抗肿瘤生长治疗的有希望的靶点。越来越多的证据表明5-氟尿嘧啶(5-FU)被掺入到功能RNA中，因此有必要研究它通过阻断假尿嘧啶酶来抑制核糖体RNA合成的作用。人类端粒酶是一种特殊的H/ACA RNP，它利用H/ACA RNA结构域进行定位和成熟。遗传病先天性角化不良(DC)是由端粒酶RNA和人类H/ACA snoRNPs四个核心蛋白中的两个突变引起的，它使患者容易患上皮癌。虽然在携带DC突变的小鼠胚胎干细胞中观察到核糖体生物发生和端粒合成方面的缺陷，但彻底了解DC突变如何影响H/ACA snoRNPs的功能将有助于理解这些突变在DC病理中的作用方式。与公共健康相关：癌细胞显示核糖体合成速度加快。识别抑制或促进核糖体合成的信号将可能揭示抗肿瘤生长治疗的有希望的靶点。

DESCRIPTION (provided by applicant): Ribosome biogenesis is an essential cellular process that must meet the demands of normal cell growth and stress responses. The foundation of ribosome biogenesis is the synthesis of ribosomal RNA. In this process, ribosomal RNA is captured, chemically modified, cleaved, and released by small nucleolar ribonucleoprotein particles (snoRNPs). Studies in my laboratory over the years suggest an emerging principle in which the single act of rRNA capture by snoRNPs encompasses multiple coordinated events occurring simultaneously with catalysis at locations distal from the active site. The multi-component yet tractable H/ACA snoRNPs offer a prototypical system for examining these interactions in detail. Our goals are to establish a mechanistic view of ribosomal RNA capture and release by snoRNPs from the initial docking through the end of chemical reactions. The proposed studies will also provide an understanding of RNA-protein composite enzymes in general at atomic details. Cancerous cells display increased ribosome synthesis. Identifying signals that inhibit or promote ribosome synthesis will potentially reveal promising targets for therapy against tumor growth. The increasing evidence that 5-fluorouracil (5-FU) is incorporated into functional RNAs necessitates investigation of its role in inhibiting ribosomal RNA synthesis by blocking pseudouridylases. Human telomerase is a specialized H/ACA RNP that exploits the H/ACA RNA domain for its localization and maturation. The genetic disease dyskeratosis congenita (DC), which predisposes patients to epithelial cancers, results from mutations in telomerase RNA and two of the four core proteins in human H/ACA snoRNPs. Although defects in both ribosome biogenesis and telomere synthesis are observed in murine embryonic stem cells bearing DC mutants, a thorough understanding of how DC mutations affect the functioning of H/ACA snoRNPs will provide an understanding of the manner in which these mutations contribute to the pathology of DC. PUBLIC HEALTH RELEVANCE: Cancerous cells display increased rate of ribosome synthesis. Identifying signals that inhibit or promote ribosome synthesis will potentially reveal promising targets for therapy against tumor growth.