Published on March 1, 2017 in Cell volume 168, 6.
PubMed ID: 28283058
Eukaryotic mRNAs generally possess a 5\' end N7\xa0methyl guanosine (mG) cap that promotes their\xa0translation and stability. However, mammalian mRNAs can also carry a 5\' end nicotinamide adenine dinucleotide (NAD) cap that, in contrast to the mG 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 mG cap that promotes rather than inhibits RNA decay.