ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion

Cell Rep. 2014 Sep 25;8(6):1819-1831. doi: 10.1016/j.celrep.2014.08.036. Epub 2014 Sep 15.


ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair
  • Energy Metabolism
  • Glycolysis / physiology*
  • Glycoside Hydrolases / antagonists & inhibitors
  • Glycoside Hydrolases / metabolism
  • Hexokinase / chemistry
  • Hexokinase / metabolism*
  • Humans
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • NAD / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Interaction Domains and Motifs
  • Proteomics
  • Sequence Alignment


  • NAD
  • Adenosine Triphosphate
  • Poly(ADP-ribose) Polymerases
  • Hexokinase
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase