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