NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

Mol Biol Cell. 2019 Sep 15;30(20):2584-2597. doi: 10.1091/mbc.E18-10-0650. Epub 2019 Aug 7.


DNA damage signaling is critical for the maintenance of genome integrity and cell fate decision. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor rapidly activated in a damage dose- and complexity-dependent manner playing a critical role in the initial chromatin organization and DNA repair pathway choice at damage sites. However, our understanding of a cell-wide consequence of its activation in damaged cells is still limited. Using the phasor approach to fluorescence lifetime imaging microscopy and fluorescence-based biosensors in combination with laser microirradiation, we found a rapid cell-wide increase of the bound NADH fraction in response to nuclear DNA damage, which is triggered by PARP-dependent NAD+ depletion. This change is linked to the metabolic balance shift to oxidative phosphorylation (oxphos) over glycolysis. Inhibition of oxphos, but not glycolysis, resulted in parthanatos due to rapid PARP-dependent ATP deprivation, indicating that oxphos becomes critical for damaged cell survival. The results reveal the novel prosurvival response to PARP activation through a change in cellular metabolism and demonstrate how unique applications of advanced fluorescence imaging and laser microirradiation-induced DNA damage can be a powerful tool to interrogate damage-induced metabolic changes at high spatiotemporal resolution in a live cell.

Publication types

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

MeSH terms

  • Cell Nucleus / metabolism
  • Cell Survival
  • DNA Damage*
  • DNA Repair*
  • Fibroblasts
  • Glycolysis / physiology
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Microscopy, Fluorescence / methods
  • NAD / metabolism*
  • Optical Imaging / methods
  • Oxidative Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Signal Transduction


  • NAD
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases