Eukaryotic RNA NAD capping and deNADding

真核 RNA NAD 加帽和 deNADding

• 批准号: 10622526
• 负责人: MEGERDITCH KILEDJIAN
• 金额: $ 36.51万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-27 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622526
• 关键词: Aging; Amino Acids; Area; Bacteria; Biological; Biological Models; Biological Process; Biology; COVID-19; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Complex; Cytoplasm; DNA; Data; Disease; Elements; Enzymes; Eukaryota; Eukaryotic Cell; Excision; Gene Expression; Genetic Transcription; Growth; Homeostasis; Human; In Vitro; Link; Mammalian Cell; Messenger RNA; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Proteins; Mitochondrial RNA; Molecular; Nicotinamide adenine dinucleotide; Nuclear; Nuclear Decay; Nuclear RNA; Nutrient; Organism; Pathway interactions; Physiological; Play; Post-Transcriptional Regulation; Process; Publishing; RNA; RNA Caps; RNA Decay; RNA Polymerase II; RNA metabolism; RNA vaccine; Regulation; Research; Respiration; Role; Saccharomyces cerevisiae; Saccharomycetales; Starvation; Stress; Testing; Therapeutic; Transcript; Virus; Work; Yeasts; decapping enzyme; defined contribution; epitranscriptomics; genetic information; insight; mitochondrial dysfunction; novel; novel strategies; nuclease; poly A specific exoribonuclease; response; senescence; sugar; transmission process

RNA 5′ end capping provides a layer of “epitranscriptomic” regulation, influencing numerous aspects of RNA fate, including stability, processing, localization and translatability. Furthermore, enzymes that remove RNA 5′ end caps play critical roles in modulating these processes. Recently, a previously unknown form of RNA 5'-end capping has been identified in bacterial, yeast, and human cells. In this new form of RNA capping, the metabolite nicotinamide adenine dinucleotide (NAD) is added at the RNA 5′ end. In contrast to 7- methylguanylate (m7G) caps, which are added to mRNAs by a complex that associates with eukaryotic RNA polymerase II (RNAP II), NAD caps are primarily added by RNAP itself in bacteria and eukaryotic nuclear and mitochondrial transcripts. Thus, unlike m7G capping, which is observed in eukaryotes and certain eukaryotic viruses, NAD capping is likely to occur in most, if not all, organisms. Our recently published work along with our unpublished preliminary data, indicates that NAD capping targets mammalian RNAs for rapid decay. In addition, we have shown eukaryotic cells possess several enzymes capable of removing NAD caps and, furthermore, that the cellular functions of these “deNADding” enzymes are most evident during metabolic stress. An overall theme emerging from our data is that addition and removal of NAD caps play critical roles in mitochondrial function where NAD-capped mitochondrial-encoded transcripts and nuclear transcripts encoding mitochondrial proteins are modulated by NAD caps. To decipher the interplay between cellular assimilation of NAD and RNA metabolism we will define the functional role(s) of NAD caps and deNADding enzymes in both budding yeast and mammalian cells. The first aim will investigate the hypothesis that NAD capping of mitochondrial RNA plays a key role in maintaining NAD homeostasis with the NAD cap serving as a reservoir to sequester and release free NAD for proper mitochondrial energetics. The second aim will investigate the impact of NAD capping on nuclear encoded RNA and, in particular, explores the hypothesis that NAD capping in budding yeast provides a mechanism for the targeted decay of RNAs in response to nutrient stress. The third aim will determine how the NAD capping and deNADding of mammalian nuclear mRNAs encoding mitochondrial proteins contributes to mitochondrial function upon cellular stress and whether perturbation of the deNADding of these mRNAs contributes to mitochondrial dysfunction associated with aging. The proposed studies will provide new insight in an emerging area of RNA biology, post- transcriptional regulation in cellular metabolism and, furthermore, may provide a mechanistic framework for developing new approaches to control gene expression in normal and disease states.

RNA 5'末端封盖提供了“同意”调节的一层，影响了RNA的许多方面 命运，包括稳定，处理，本地化和转换性。此外，去除RNA的酶 5'端盖在调节这些过程中起关键作用。最近，一种先前未知的RNA形式 在细菌，酵母和人类细胞中已经确定了5'末端封盖。在这种新形式的RNA封盖中， 在RNA 5'端添加了代谢物烟酰胺腺苷二核苷酸（NAD）。与7-相反 甲基鸟苯甲酸酯（M7G）盖，由与真核RNA相关的复合物添加到mRNA中 聚合酶II（RNAP II），NAD帽主要由RNAP本身添加在细菌和真核核中，以及 线粒体转录本。与M7G封盖不同，这在真核生物和某些真核生物中观察到 病毒，NAD上限可能会在大多数（如果不是全部）生物中发生。我们最近发表的作品以及 我们未发表的初步数据表明，NAD上限目标是哺乳动物RNA快速衰减。 此外，我们显示的真核细胞具有几种能够去除NAD帽的酶，并且，，，，， 此外，这些“剥皮”酶的细胞功能是代谢过程中最证据的证据 压力。从我们的数据中出现的总体主题是，添加和去除NAD帽子起着关键的作用 在线粒体函数中，其中NAD限制的线粒体编码的转录本和核转录本 编码线粒体蛋白由NAD帽调节。破译细胞之间的相互作用 NAD和RNA代谢的同化我们将定义NAD帽和剥落的功能作用 萌芽的酵母菌和哺乳动物细胞中的酶。第一个目的将调查NAD的假设 线粒体RNA的上限在维持NAD稳态的NAD帽中起着关键作用 用于隔离和释放自由NAD的水库，以进行适当的线粒体能量学。第二个目标 研究NAD盖对核编码RNA的影响，尤其是探讨了假设 在发芽的酵母中，NAD上限为RNA的靶向衰减提供了一种机制 营养应激。第三个目标将决定哺乳动物核的NAD封盖和底漆 编码线粒体蛋白的mRNA在细胞应激和 这些mRNA的扰动是否有助于线粒体功能障碍相关 随着衰老。拟议的研究将在RNA生物学的新兴领域提供新的见解。 细胞代谢中的转录调节，此外，可以为机械框架提供机械框架 开发新的方法来控制正常和疾病状态中的基因表达。