5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding.
Publication Type:Journal Article
Source:Cell, Volume 168, Issue 6, p.1015-1027.e10 (2017)
Keywords:Animals, Endoribonucleases, HEK293 Cells, Humans, Mice, NAD, Nuclear Proteins, Protein Biosynthesis, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Messenger, RNA, Untranslated
<p>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.</p>