Non-Coding RNPs: From RNA Modification to Genome Defense

描述（由申请人提供）：最近在生物学和医学中最重要的认识之一是非编码rna （ncRNAs）在许多重要的生物学过程中发挥的关键作用，包括基因表达的许多方面。不出所料，ncRNA功能对人类健康和疾病的影响被证明是广泛而实质性的。大多数非编码rna与伴侣蛋白组装形成非编码rna -蛋白复合物（ncRNPs），这些复合物在多种细胞过程中发挥作用。本提案的主要目的是通过生化和分子分析来详细了解两种不同且重要的ncRNPs的生物发生和功能。我们的第一个目标是确定H/ACA RNP的四种必需蛋白和引导RNA如何组装和共同作用以进行RNA修饰。在人类中，H/ACA RNPs是产生前mrna剪接和蛋白质翻译机制以及基因组稳定性所必需的。我们对这个复合体的研究为先天性干酪化异常的病因学提供了新的见解。在我们的第二个目标中提出的实验将提供有关新认识的原核基因组防御系统的生物发生和功能的大量信息。该途径与原核生物（包括重要的人类病原体）对病毒和其他可移动遗传元件的防御密切相关。该系统代表了一种主要的新的RNA沉默途径，具有为其他沉默途径提供见解的潜力。重要的是，这一途径可能为实验基因沉默和开发在广泛的原核生物中有效的新型治疗方法提供了一种手段，其中发现了该系统。总的来说，拟议的研究具有对人类健康和疾病作出重大贡献的巨大潜力。

DESCRIPTION (provided by applicant): One of the most significant recent realizations in biology and medicine is the key role that noncoding RNAs (ncRNAs) play in numerous and important biological processes including many aspects of gene expression. Not surprisingly, the impact of ncRNA function on human health and disease is proving to be broad and substantial. Most non-coding RNAs assemble with partner proteins to form non-coding RNA-protein complexes (ncRNPs), and these function in diverse cellular processes. The major objective of this proposal is to obtain a detailed understanding of the biogenesis and function of two distinct and important classes of ncRNPs through biochemical and molecular analysis. Our first aim is to determine how the four essential proteins and guide RNA of the H/ACA RNP assemble and function together to carry out RNA modification. In humans, H/ACA RNPs are required for the production of the pre-mRNA splicing and protein translation machinery as well as for genome stability. Our work on this complex has provided new insight into the etiology of dyskerotosis congenita. The experiments proposed in our second aim will provide substantial information on the biogenesis and function of a newly recognized prokaryotic genome defense system. This pathway is strongly implicated in defense against viruses and other mobile genetic elements in prokaryotes including important human pathogens. This system represents a major new RNA silencing pathway with the potential to provide insight on other silencing pathways. Importantly, this pathway may provide a means for both experimental gene silencing and development of novel classes of therapeutics effective in the broad range of prokaryotes in which the system is found. Together, the proposed studies have great potential for significant contributions to human health and disease.