Eukaryotic RNA NAD capping and deNADding

真核 RNA NAD 加帽和 deNADding

• 批准号: 10797880
• 负责人: MEGERDITCH KILEDJIAN
• 金额: $ 3.35万
• 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/10797880
• 关键词: Aging; Area; Bacteria; Biology; COVID-19; Cell physiology; Cells; Cellular Stress; Complex; DNA; Data; Disease; Elements; Enzymes; Eukaryota; Eukaryotic Cell; Excision; Funding; Gene Expression; Grant; Homeostasis; Human; Mammalian Cell; Messenger RNA; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Proteins; Mitochondrial RNA; Molecular; Nicotinamide adenine dinucleotide; Nuclear; Nutrient; Organism; Play; Post-Transcriptional Regulation; Process; Publishing; RNA; RNA Caps; RNA Decay; RNA Polymerase II; RNA metabolism; RNA vaccine; Regulation; Role; Saccharomycetales; Stress; Therapeutic; Transcript; Virus; Work; Yeasts; epitranscriptomics; genetic information; insight; mitochondrial dysfunction; novel; novel strategies; response; transmission process

Project Summary of the funded parental grant GM126488: 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 Our recently published work along with our unpublished preliminary data, indicates that NAD capping targets mammalian RNAs for rapid decay.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.

获资助父母资助GM126488项目总结：

项目成果

Xrn1 is a deNADding enzyme modulating mitochondrial NAD-capped RNA.

• DOI: 10.1038/s41467-022-28555-7
• 发表时间: 2022-02-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Sharma S;Yang J;Grudzien-Nogalska E;Shivas J;Kwan KY;Kiledjian M
• 通讯作者: Kiledjian M

InsP7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics

• DOI: 10.1073/pnas.1922284117
• 发表时间: 2020-08-11
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Sahu, Soumyadip;Wang, Zhenzhen;Shears, Stephen B.
• 通讯作者: Shears, Stephen B.

Identification of a novel deFADding activity in human, yeast and bacterial 5' to 3' exoribonucleases.

• DOI: 10.1093/nar/gkac617
• 发表时间: 2022-08-26
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Sharma, Sunny;Yang, Jun;Doamekpor, Selom K.;Grudizen-Nogalska, Ewa;Tong, Liang;Kiledjian, Megerditch
• 通讯作者: Kiledjian, Megerditch

Recent insights into noncanonical 5' capping and decapping of RNA.

• DOI: 10.1016/j.jbc.2022.102171
• 发表时间: 2022-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Doamekpor, Selom K.;Sharma, Sunny;Kiledjian, Megerditch;Tong, Liang
• 通讯作者: Tong, Liang

mRNA-Decapping Associated DcpS Enzyme Controls Critical Steps of Neuronal Development.

mRNA 脱帽相关 DcpS 酶控制神经元发育的关键步骤。

• DOI: 10.1093/cercor/bhab302
• 发表时间: 2022
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Salamon,Iva;Palsule,Geeta;Luo,Xiaobing;Roque,Alfonso;Tucai,Shawn;Khosla,Ishan;Volk,Nicole;Liu,Wendy;Cui,Huijuan;Pozzo,ValentinaDal;Zalamea,Petronio;Jiao,Xinfu;D'Arcangelo,Gabriella;Hart,RonaldP;Rasin,Mladen-Roko;Kiledjian,
• 通讯作者: Kiledjian,