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

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

Author information

1
Department of Biomedical Engineering, School of Engineering, University of California, Irvine, Irvine, CA 92697.
2
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697.
3
Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, CA 92697.
4
Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697.
5
UC Irvine Diabetes Center, University of California, Irvine, Irvine, CA 92697.
6
Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.

Abstract

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.

PMID:
31390283
PMCID:
PMC6740200
DOI:
10.1091/mbc.E18-10-0650

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