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      Structural and mechanistic basis of the mammalian Nudt12 RNA deNADding

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          Abstract

          We recently demonstrated mammalian cells harbor NAD-capped mRNAs that are hydrolyzed by the DXO deNADding enzyme. Here we report the Nudix protein Nudt12 is a second mammalian deNADding enzyme structurally and mechanistically distinct from DXO and targeting different RNAs. Crystal structure of mouse Nudt12 in complex with the deNADding product AMP and three Mg 2+ ions at 1.6 Å resolution provides exquisite insights into the molecular basis of the deNADding activity within the NAD pyrophosphate. Disruption of the Nudt12 gene stabilizes transfected NAD-capped RNA in cells and its endogenous NAD-capped mRNA targets are enriched in those encoding proteins involved in cellular energetics. Furthermore, exposure of cells to nutrient or environmental stress manifests changes in NAD-capped RNA levels that are selectively responsive to Nudt12 or DXO respectively, indicating an association of deNADding to cellular metabolism.

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          Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt.

          Marcella Fulco, Yana Cen, Po Zhao … (2008)
          It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]:[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1+/- heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability.
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            NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs.

            Hana Cahová, Marie-Luise Winz, Katharina Höfer … (2015)
            A distinctive feature of prokaryotic gene expression is the absence of 5'-capped RNA. In eukaryotes, 5',5'-triphosphate-linked 7-methylguanosine protects messenger RNA from degradation and modulates maturation, localization and translation. Recently, the cofactor nicotinamide adenine dinucleotide (NAD) was reported as a covalent modification of bacterial RNA. Given the central role of NAD in redox biochemistry, posttranslational protein modification and signalling, its attachment to RNA indicates that there are unknown functions of RNA in these processes and undiscovered pathways in RNA metabolism and regulation. The unknown identity of NAD-modified RNAs has so far precluded functional analyses. Here we identify NAD-linked RNAs from bacteria by chemo-enzymatic capture and next-generation sequencing (NAD captureSeq). Among those identified, specific regulatory small RNAs (sRNAs) and sRNA-like 5'-terminal fragments of certain mRNAs are particularly abundant. Analogous to a eukaryotic cap, 5'-NAD modification is shown in vitro to stabilize RNA against 5'-processing by the RNA-pyrophosphohydrolase RppH and against endonucleolytic cleavage by ribonuclease (RNase) E. The nudix phosphohydrolase NudC decaps NAD-RNA and thereby triggers RNase-E-mediated RNA decay, while being inactive against triphosphate-RNA. In vivo, ∼13% of the abundant sRNA RNAI is NAD-capped in the presence, and ∼26% in the absence, of functional NudC. To our knowledge, this is the first description of a cap-like structure and a decapping machinery in bacteria.
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              5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding.

              Xinfu Jiao, Selom Doamekpor, Jeremy G Bird … (2017)
              Eukaryotic mRNAs generally possess a 5' end N7 methyl guanosine (m(7)G) cap that promotes their translation and stability. However, mammalian mRNAs can also carry a 5' end nicotinamide adenine dinucleotide (NAD(+)) cap that, in contrast to the m(7)G cap, does not support translation but instead promotes mRNA decay. The mammalian and fungal noncanonical DXO/Rai1 decapping enzymes efficiently remove NAD(+) caps, and cocrystal structures of DXO/Rai1 with 3'-NADP(+) illuminate the molecular mechanism for how the "deNADding" reaction produces NAD(+) and 5' phosphate RNA. Removal of DXO from cells increases NAD(+)-capped mRNA levels and enables detection of NAD(+)-capped intronic small nucleolar RNAs (snoRNAs), suggesting NAD(+) caps can be added to 5'-processed termini. Our findings establish NAD(+) as an alternative mammalian RNA cap and DXO as a deNADding enzyme modulating cellular levels of NAD(+)-capped RNAs. Collectively, these data reveal that mammalian RNAs can harbor a 5' end modification distinct from the classical m(7)G cap that promotes rather than inhibits RNA decay.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101231976
                Journal ID (pubmed-jr-id): 32624
                Journal ID (nlm-ta): Nat Chem Biol
                Journal ID (iso-abbrev): Nat. Chem. Biol.
                Title: Nature chemical biology
                ISSN (Print): 1552-4450
                ISSN (Electronic): 1552-4469
                Publication date Nihms-submitted: 18 March 2019
                Publication date (Electronic): 17 May 2019
                Publication date (Print): June 2019
                Publication date PMC-release: 17 November 2019
                Volume: 15
                Issue: 6
                Pages: 575-582
                Affiliations
                [1 ]Department Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854
                [2 ]Department Biological Sciences, Columbia University, New York, NY 10027
                [3 ]These authors contributed equally to this work.
                Author notes
                [* ]Correspondence should be addressed to: Megerditch Kiledjian, Phone: (848) 445-0796, kiledjian@ 123456biology.rutgers.edu , Liang Tong, Phone: (212) 854-5203, ltong@ 123456columbia.edu

                AUTHOR CONTRIBUTIONS

                M.K., E.G.N., and L.T. designed the experiments. E.G.N. carried out all experiments unless otherwise indicated. X.J. and H.C. created N12 and N12:DXO CRISPR knockout cell lines. X.J. carried out the initial NAD captureSeq and the assays in Fig. 2. Y.W. and L.T. carried out the structural analysis and interpretations. M.K.M. carried out experiments in Fig S4. R.P.H. carried out all bioinformatics analyses. E.G.N. M.K., L.T., Y.W. and R.P.H. wrote the manuscript.

                Article
                Manuscript ID: NIHMS1524236
                DOI: 10.1038/s41589-019-0293-7
                PMC ID: 6527130
                PubMed ID: 31101919
                SO-VID: 90261993-0c02-4c5f-8c3f-a76dd1ed6bf3
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                ScienceOpen disciplines: Biochemistry
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                ScienceOpen disciplines: Biochemistry

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