ATM induces MacroD2 nuclear export upon DNA damage

Nucleic Acids Res. 2017 Jan 9;45(1):244-254. doi: 10.1093/nar/gkw904. Epub 2016 Oct 7.


ADP-ribosylation is a dynamic post-translation modification that regulates the early phase of various DNA repair pathways by recruiting repair factors to chromatin. ADP-ribosylation levels are defined by the activities of specific transferases and hydrolases. However, except for the transferase PARP1/ARDT1 little is known about regulation of these enzymes. We found that MacroD2, a mono-ADP-ribosylhydrolase, is exported from the nucleus upon DNA damage, and that this nuclear export is induced by ATM activity. We show that the export is dependent on the phosphorylation of two SQ/TQ motifs, suggesting a novel direct interaction between ATM and ADP-ribosylation. Lastly, we show that MacroD2 nuclear export temporally restricts its recruitment to DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at the site of DNA damage. Together, our results identify a novel feedback regulation between two crucial DNA damage-induced signaling pathways: ADP-ribosylation and ATM activation.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adenosine Diphosphate / metabolism*
  • Amino Acid Motifs
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • DNA Damage*
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Feedback, Physiological
  • HeLa Cells
  • Humans
  • Hydrolases / genetics*
  • Hydrolases / metabolism
  • Osteoblasts
  • Phosphorylation
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Processing, Post-Translational*
  • Signal Transduction


  • MACROD2 protein, human
  • Adenosine Diphosphate
  • Poly(ADP-ribose) Polymerases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Hydrolases
  • DNA Repair Enzymes