Non-Coding RNPs: From RNA Modification to Genome Defense

描述(申请人提供)：生物学和医学中最重要的最新认识之一是非编码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。毫不奇怪，事实证明，ncRNA功能对人类健康和疾病的影响是广泛和实质性的。大多数非编码RNA与伙伴蛋白组装形成非编码RNA-蛋白质复合体(NcRNPs)，这些复合体在不同的细胞过程中发挥功能。这项建议的主要目的是通过生化和分子分析来详细了解两类不同和重要的ncRNPs的生物发生和功能。我们的第一个目标是确定H/ACA RNP的四种基本蛋白质和指导RNA是如何组装在一起并发挥作用的，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。我们在这个复合体上的工作为先天性肌萎缩症的病因学提供了新的见解。我们第二个目标中提出的实验将提供关于新发现的原核生物基因组防御系统的生物发生和功能的大量信息。原核生物包括重要的人类病原体在内的原核生物中，这一途径与防御病毒和其他可移动的遗传元件密切相关。该系统代表了一个重要的新的RNA沉默途径，有可能为其他沉默途径提供洞察力。重要的是，这一途径可能为实验性的基因沉默和开发在发现该系统的广泛原核生物中有效的新型治疗方法提供一种手段。总之，拟议的研究具有对人类健康和疾病做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.