Non-Coding RNPs: From RNA Modification to Genome Defense

非编码 RNP：从 RNA 修饰到基因组防御

• 批准号: 7892747
• 负责人: MICHAEL P TERNS
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892747
• 关键词: Base Pairing; Biochemical; Biogenesis; Bioinformatics; Biological; Biological Process; Biology; Cell physiology; Cells; Clinical; Complex; Defense Mechanisms; Development; Diagnostic; Disease; Dyskeratosis Congenita; Etiology; Eukaryota; Foundations; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genome; Genome Stability; Guide RNA; Hand; Health; Human; Investigation; Link; Malignant Neoplasms; Mediating; Medicine; Mobile Genetic Elements; Modeling; Modification; Molecular; Molecular Analysis; Nucleic Acids; Pathway interactions; Play; Process; Production; Prokaryotic Cells; Protein Splicing; Proteins; RNA; RNA Interference; RNA Processing; Role; Small Nuclear RNA; Spinal Muscular Atrophy; System; Therapeutic; Therapeutic Agents; Translations; Untranslated RNA; Virus; Work; base; falls; insight; interest; loss of function; mRNA Precursor; nervous system disorder; novel; pathogen; protein complex; research study; trafficking

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.

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（ncRNA）在许多重要的生物学过程（包括基因表达的许多方面）中发挥的关键作用。毫不奇怪，ncRNA功能对人类健康和疾病的影响被证明是广泛和实质性的。大多数非编码RNA与伴侣蛋白组装形成非编码RNA-蛋白质复合物（ncRNP），并且这些在不同的细胞过程中起作用。该提案的主要目标是通过生物化学和分子分析，详细了解两种不同且重要的ncRNP的生物起源和功能。我们的第一个目标是确定H/ACA RNP的四个必需蛋白质和指导RNA如何组装和功能在一起以进行RNA修饰。在人类中，H/ACA RNP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。我们对这一复合体的研究为先天性角化障碍的病因学提供了新的认识。在我们的第二个目标提出的实验将提供大量的信息，一个新认识的原核基因组防御系统的生物起源和功能。该途径强烈地涉及原核生物包括重要的人类病原体中对病毒和其他移动的遗传元件的防御。该系统代表了一种主要的新RNA沉默途径，具有提供对其他沉默途径的了解的潜力。重要的是，这一途径可能为实验性基因沉默和开发新的治疗方法提供一种手段，这些方法在发现该系统的广泛原核生物中有效。