A family of macrodomain proteins reverses cellular mono-ADP-ribosylation

Nat Struct Mol Biol. 2013 Apr;20(4):508-14. doi: 10.1038/nsmb.2523. Epub 2013 Mar 10.


ADP-ribosylation is a reversible post-translational modification with wide-ranging biological functions in all kingdoms of life. A variety of enzymes use NAD(+) to transfer either single or multiple ADP-ribose (ADPr) moieties onto distinct amino acid substrates, often in response to DNA damage or other stresses. Poly-ADPr-glycohydrolase readily reverses poly-ADP-ribosylation induced by the DNA-damage sensor PARP1 and other enzymes, but it does not remove the most proximal ADPr linked to the target amino acid. Searches for enzymes capable of fully reversing cellular mono-ADP-ribosylation back to the unmodified state have proved elusive, which leaves a gap in the understanding of this modification. Here, we identify a family of macrodomain enzymes present in viruses, yeast and animals that reverse cellular ADP-ribosylation by acting on mono-ADP-ribosylated substrates. Our discoveries establish the complete reversibility of PARP-catalyzed cellular ADP-ribosylation as a regulatory modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism*
  • Amino Acid Sequence
  • Biocatalysis
  • Models, Molecular
  • Molecular Sequence Data
  • N-Glycosyl Hydrolases / chemistry
  • N-Glycosyl Hydrolases / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational
  • Proteins / metabolism*
  • Sequence Homology, Amino Acid


  • Proteins
  • Adenosine Diphosphate Ribose
  • N-Glycosyl Hydrolases
  • ADP-ribosylarginine hydrolase

Associated data

  • PDB/4IQY