5’ end RNA Caps in Gene Expression

项目摘要 建议的研究集中于我们描绘功能贡献的长期努力。 典型和非典型核苷酸代谢产物mRNA5的末端封端及其在体内的去除 控制RNA的稳定性和基因表达。核糖核酸周转的调控是 基因表达的调节和mRNA稳定性的微小变化可能会产生深远的影响 结果，并可能表现为临床表型。一个控制命运的关键组件 真核细胞的mRNA5‘端为顶端。真核生物的帽子通常被认为具有规范的 N7甲基鸟苷(M7G)位于其5°端，以促进其稳定性和转译。移除 M7G帽的部分(去盖)被精心调控，使RNA在翻译上保持沉默 容易迅速腐烂和基因沉默。此外，最近出现了一种令人兴奋的范式转变 证明了真核RNA也可以携带非规范的5‘端核苷酸 代谢物帽子，最初是烟酰胺腺嘌呤二磷酸(NAD)，然后是黄素 腺嘌呤二核苷酸(FAD)和尿苷二磷酸N-乙酰氨基葡萄糖(UDP-GlcNAc)。是这样的 CAPS在RNA新陈代谢和细胞新陈代谢之间提供了潜在的联系。然而，在那里 是我们对这些新型帽子及其生理功能的理解上的一大差距 作为他们的明确身份。因此，对个人的详细机械理解 新型核苷酸代谢物封端RNA及其对细胞能量学的功能影响 基因表达将对处于正常和疾病状态的细胞产生广泛的影响。

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.