Structural and mechanistic basis of mammalian Nudt12 RNA deNADding

Nat Chem Biol. 2019 Jun;15(6):575-582. doi: 10.1038/s41589-019-0293-7. Epub 2019 May 17.


We recently demonstrated that mammalian cells harbor nicotinamide adenine dinucleotide (NAD)-capped messenger RNAs that are hydrolyzed by the DXO deNADding enzyme. Here, we report that the Nudix protein Nudt12 is a second mammalian deNADding enzyme structurally and mechanistically distinct from DXO and targeting different RNAs. The crystal structure of mouse Nudt12 in complex with the deNADding product AMP and three Mg2+ ions at 1.6 Å resolution provides insights into the molecular basis of the deNADding activity in the NAD pyrophosphate. Disruption of the Nudt12 gene stabilizes transfected NAD-capped RNA in cells, and its endogenous NAD-capped mRNA targets are enriched in those encoding proteins involved in cellular energetics. Furthermore, exposure of cells to nutrient or environmental stress manifests changes in NAD-capped RNA levels that are selectively responsive to Nudt12 or DXO, respectively, indicating an association of deNADding to cellular metabolism.

Publication types

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

MeSH terms

  • Humans
  • NAD / chemistry
  • NAD / metabolism*
  • Pyrophosphatases / chemistry
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism*
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*


  • RNA, Messenger
  • NAD
  • NUDT12 protein, human
  • Pyrophosphatases