Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 30, Issue 20, Pages 2584-2597Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E18-10-0650
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Funding
- National Institutes of Health (NIH) [P41-GM103540]
- National Science Foundation [MCB-1615701]
- UCI Academic Senate Council on Research, Computing & Library (CORCL)
- Cancer Research Coordinating Committee (CRCC)
- Air Force (AFOSR) [FA9550-08-1-0384]
- Hoag Family Foundation, Huntington Beach, CA
- David and Lucille Packard FoundationLos Altos, CA
- National Heart, Lung, and Blood Institute [R01 HL096987]
- Fatima Foundation
- Chao Family Comprehensive Cancer Center Optical Biology Core (LAMMP/OBC) Shared Resource
- National Cancer Institute of the NIH [P30CA062203]
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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.
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