Structure and Regulation of snoRNP Interaction with rRNA

描述（由申请人提供）：核糖体生物发生是一个必要的细胞过程，必须满足正常细胞生长和应激反应的需要。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被捕获，化学修饰，切割，并由小核仁核糖核蛋白颗粒（snoRNPs）释放。我的实验室多年来的研究表明，一个新兴的原理是，snornp捕获rRNA的单一行为包含多个协调的事件，同时发生在活性位点远端的催化位置。多组分但易于处理的H/ACA snornp为详细检查这些相互作用提供了一个原型系统。我们的目标是建立从初始对接到化学反应结束，snornp捕获和释放核糖体RNA的机制观点。提出的研究也将提供对rna -蛋白复合酶在原子细节上的一般理解。癌细胞显示核糖体合成增加。识别抑制或促进核糖体合成的信号将潜在地揭示治疗肿瘤生长的有希望的靶点。越来越多的证据表明，5-氟尿嘧啶（5-FU）被纳入功能性RNA中，有必要研究其通过阻断假尿嘧啶酶抑制核糖体RNA合成的作用。人类端粒酶是一种特殊的H/ACA RNP，利用H/ACA RNA结构域进行定位和成熟。遗传性疾病先天性角化不良（DC），使患者易患上皮癌，是端粒酶RNA和人类H/ACA snoRNPs中四个核心蛋白中的两个发生突变的结果。尽管在携带DC突变体的小鼠胚胎干细胞中观察到核糖体生物发生和端粒合成的缺陷，但深入了解DC突变如何影响H/ACA snoRNPs的功能将有助于了解这些突变如何导致DC病理。公共卫生相关性：癌细胞显示核糖体合成速率增加。识别抑制或促进核糖体合成的信号将潜在地揭示治疗肿瘤生长的有希望的靶点。

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.