title: 5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding.
abstract: Eukaryotic mRNAs generally possess a 5' end N7 methyl guanosine (m7G) 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 m7G 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 m7G cap that promotes rather than inhibits RNA decay.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Selom K
authors.initials: SK
authors.lastname: Doamekpor
authors.affiliation: Department of Genetics and Waksman Institute, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Bird
authors.affiliation: Department of Genetics and Waksman Institute, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Bryce E
authors.initials: BE
authors.lastname: Nickels
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: kiledjian@biology.rutgers.edu.
authors.forename: Megerditch
authors.initials: M
authors.lastname: Kiledjian
mesh_terms: D000818:Animals; D004722:Endoribonucleases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009243:NAD / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism
chemical_list: C581516:Dom3Z protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; C030052:mRNA decapping enzymes; D009243:NAD; D004722:Endoribonucleases; C467723:DCP2 protein, human