Decapping Enzyme NUDT12 Partners with BLMH for Cytoplasmic Surveillance of NAD-Capped RNAs

Cell Rep. 2019 Dec 24;29(13):4422-4434.e13. doi: 10.1016/j.celrep.2019.11.108.


RNA polymerase II transcripts receive a protective 5',5'-triphosphate-linked 7-methylguanosine (m7G) cap, and its removal by decapping enzymes like DCP2 is critical for initiation of RNA decay. Alternative RNA caps can be acquired when transcription initiation uses metabolites like nicotinamide adenine dinucleotide (NAD), generating NAD-RNAs. Here, we identify human NUDT12 as a cytosolic NAD-RNA decapping enzyme. NUDT12 is active only as homodimers, with each monomer contributing to creation of the two functional catalytic pockets. We identify an ∼600-kDa dodecamer complex between bleomycin hydrolase (BLMH) and NUDT12, with BLMH being required for localization of NUDT12 to a few discrete cytoplasmic granules that are distinct from P-bodies. Both proteins downregulate gene expression when artificially tethered to a reporter RNA in vivo. Furthermore, loss of Nudt12 results in a significant upregulation of circadian clock transcripts in mouse liver. Overall, our study points to a physiological role for NUDT12 in the cytosolic surveillance of NAD-RNAs.

Keywords: BLMH; NAD-RNA; RNA decay; circadian clock; deNADding; human NUDT12; m(7)G.

MeSH terms

  • Animals
  • Ankyrin Repeat
  • Biocatalysis
  • Circadian Clocks / genetics
  • Cysteine Endopeptidases / metabolism*
  • Cytoplasm / metabolism*
  • Cytoplasmic Granules / metabolism
  • Endoribonucleases / metabolism*
  • Enzyme Stability
  • Guanosine / analogs & derivatives
  • Guanosine / metabolism
  • HeLa Cells
  • Humans
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Weight
  • NAD / metabolism*
  • Protein Multimerization
  • Pyrophosphatases / chemistry
  • Pyrophosphatases / metabolism*
  • RNA Caps / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • RNA Caps
  • RNA, Messenger
  • mRNA decapping enzymes
  • NAD
  • Guanosine
  • 7-methylguanosine
  • Endoribonucleases
  • Cysteine Endopeptidases
  • bleomycin hydrolase
  • NUDT12 protein, human
  • Nudt12 protein, mouse
  • Pyrophosphatases