Identification and Characterization of Small Molecule-RNA Conjugates in Yeast

酵母中小分子 RNA 缀合物的鉴定和表征

• 批准号: 8113911
• 负责人: Aaron Morgan Leconte
• 金额: $ 4.77万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113911
• 关键词: Animal Model; Area; Bacteria; Biological; Biological Process; Biology; Catalysis; Catalytic RNA; Cell physiology; Cells; Chemical Structure; Chemicals; Computing Methodologies; Development; Drug Delivery Systems; Eukaryota; Fission Yeast; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Proteins; Laboratories; Lead; Link; Methods; MicroRNAs; Modeling; Modification; Nucleotides; Organism; Play; Procedures; Protein Biosynthesis; RNA; RNA Sequences; Reporting; Research; Ribonucleotides; Role; Saccharomyces cerevisiae; Screening procedure; Signal Transduction; Small Interfering RNA; Spliced Genes; Structure; Transfer RNA; Yeasts; base; biological systems; chemical function; improved; insight; new therapeutic target; novel; public health relevance; small molecule

DESCRIPTION (provided by applicant): Over the past few decades, the discovery of a wide range of functional RNAs has revealed an expanding role for RNA in essential cellular processes such as gene expression and protein biosynthesis; however, the known chemical diversity available to RNA is still relatively limited. Traditionally, the discovery of chemically modified ribonucleotides in biological systems has been limited to a target based approach; either the class of RNA molecules or the nucleotide modification were known beforehand and studied in a limited context. Recently, a general screen has been reported for the discovery of small molecule-RNA conjugates. Unlike previous methods, this screen is not dependent on a specific small-molecule structure, on a certain class of RNA, or on a particular biological function of the conjugate. The identification of novel chemical modifications of RNA has the potential to improve our still relatively poor understanding of RNA biology in areas such as gene regulation or gene splicing, and, more provocatively, may identify entirely new roles for RNA in the cell, such as new modes of catalysis, signaling, or gene regulation. Previously, application of this approach led to the discovery of two novel 5' small molecule-RNA conjugates in two bacterial organisms. Here, the screen will be used to identify modified nucleotides present in yeast. Following identification, focus will be placed on characterizing the biological function of the modified nucleotides through development of sequencing methods for modified RNAs as well as attempting to link the modified RNA to a known biological process. The proposed research has the potential to provide a more complete understanding of the chemical diversity of cellular RNA in yeast, and possibly significantly expand our understanding of the biological, and perhaps even chemical, functions of RNA. PUBLIC HEALTH RELEVANCE: The known biological roles of cellular RNA have expanded considerably in the past few decades; however, the chemical diversity of RNA has remained relatively constant. This proposal seeks to identify novel modified RNA in yeast, an important eukaryotic model organism, and characterize their biological function. An increased understanding of the chemical diversity of RNA will potentially improve understanding of the biological role of RNA, and, eventually, lead to new therapeutic targets.

描述（由申请人提供）：在过去的几十年中，广泛的功能性RNA的发现揭示了RNA在基本细胞过程如基因表达和蛋白质生物合成中的作用不断扩大;然而，RNA可用的已知化学多样性仍然相对有限。传统上，在生物系统中发现化学修饰的核糖核苷酸仅限于基于靶点的方法; RNA分子的类别或核苷酸修饰是预先已知的，并且在有限的背景下进行研究。最近，已经报道了用于发现小分子-RNA缀合物的一般筛选。与以前的方法不同，这种筛选不依赖于特定的小分子结构、特定类别的RNA或缀合物的特定生物学功能。RNA的新化学修饰的鉴定有可能改善我们在基因调控或基因剪接等领域对RNA生物学的相对较差的理解，并且更有可能确定RNA在细胞中的全新角色，例如新的催化模式，信号传导或基因调控。以前，这种方法的应用导致在两种细菌生物体中发现两种新的5'小分子-RNA缀合物。在这里，筛选将用于鉴定酵母中存在的修饰的核苷酸。鉴定后，重点将放在通过开发修饰RNA的测序方法来表征修饰核苷酸的生物学功能，以及尝试将修饰RNA与已知的生物学过程联系起来。拟议的研究有可能提供对酵母细胞RNA化学多样性的更完整的理解，并可能显着扩大我们对RNA的生物学甚至化学功能的理解。 公共卫生相关性：在过去的几十年里，细胞RNA的已知生物学作用已经大大扩展;然而，RNA的化学多样性仍然相对稳定。该提案旨在鉴定酵母（一种重要的真核模式生物）中新型修饰RNA，并表征其生物学功能。对RNA化学多样性的进一步了解将可能提高对RNA生物学作用的理解，并最终导致新的治疗靶点。