NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival
MM Murata, X Kong, E Moncada, Y Chen… - Molecular biology of …, 2019 - molbiolcell.org
Molecular biology of the cell, 2019•molbiolcell.org
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 …
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 …
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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