5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding

Cell. 2017 Mar 9;168(6):1015-1027.e10. doi: 10.1016/j.cell.2017.02.019.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Endoribonucleases / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • NAD / metabolism
  • Nuclear Proteins / metabolism
  • Protein Biosynthesis
  • RNA Processing, Post-Transcriptional*
  • RNA Stability*
  • RNA, Messenger / metabolism
  • RNA, Untranslated / metabolism


  • Dom3Z protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • RNA, Untranslated
  • mRNA decapping enzymes
  • NAD
  • Endoribonucleases
  • DCP2 protein, human