5’ end RNA Caps in Gene Expression

项目摘要 拟议的研究集中在我们的长期努力，以描绘功能的贡献， 典型和非典型核苷酸代谢产物mRNA 5端帽的表达及其在细胞中的去除 控制RNA稳定性和基因表达。RNA周转的调节是细胞增殖的关键步骤。 基因表达的调节和mRNA稳定性的微小改变可以产生深远的影响。 结果，并可能表现为临床表型。一个关键的组成部分， 真核生物mRNA是5 ′端帽。真核细胞帽通常被认为具有典型的 N7甲基鸟苷（m7 G）在其5 ′-端加帽以促进其稳定性和翻译。去除 m7 G帽（脱帽）的表达受到精细调控，使RNA沉默， 会迅速腐烂和基因沉默。此外，最近出现了一个令人兴奋的范式转变， 证明真核RNA也可以携带非典型的5 ′端核苷酸， 代谢物帽，最初是烟酰胺腺嘌呤二磷酸（NAD），随后是黄素 腺嘌呤二核苷酸（FAD）和尿苷二磷酸N-乙酰葡糖胺（UDP-GlcNAc）。等 帽提供了RNA代谢和细胞代谢之间的潜在联系。但 是我们对这些新帽子及其生理功能的理解中的一个主要空白 作为他们明确的身份。因此，对个体的详细机械理解 新的核苷酸代谢物加帽RNA及其对细胞能量学的功能影响 并且基因表达将对正常和疾病状态的细胞具有广泛的影响。

Project Summary The proposed studies are focused on our long-term effort to delineate the functional contribution of canonical and non-canonical nucleotide metabolite mRNA 5¢ end caps and their removal in the control of RNA stability and gene expression. Regulation of RNA turnover is a critical step in the modulation of gene expression and minor alterations in mRNA stability can have profound consequences and may manifest as clinical phenotypes. A key component controlling the fate of eukaryotic mRNA is the 5¢-end cap. Eukaryotic caps are generally thought to possess a canonical N7 methyl guanosine (m7G) cap at their 5¢-end to promote their stability and translation. Removal of the m7G cap (decapping) is exquisitely regulated and renders the RNA translationally silent and subject to rapid decay and gene silencing. Moreover, a recent exciting paradigm shift emerged with the demonstration that eukaryotic RNAs can also carry noncanonical 5´end nucleotide metabolite caps, initially of nicotinamide adenine diphosphate (NAD) and subsequently flavin adenine dinucleotide (FAD) and Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Such caps provide a potential link between RNA metabolism and cellular metabolism. However, there is a major gap in our understanding of these novel caps and their physiological function as well as their unambiguous identification. Thus, a detailed mechanistic understanding of the individual novel nucleotide metabolite capped RNAs and their functional consequence on cellular energetics and gene expression will have broad implications for cells in both normal and disease states.