5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding.
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.
Jiao X, Doamekpor SK, Bird JG, Nickels BE, Tong L, Hart RP, Kiledjian M