Alkylating DNA damage stimulates a regulated form of necrotic cell death

TLDR

Necrosis has long been viewed as a passive, bioenergetic catastrophe, yet alkylating DNA damage induces a self‑determined necrotic fate. DNA‑damage–induced necrosis requires PARP activation, but the outcome is governed by PARP‑driven NAD depletion that disrupts cellular metabolism. Alkylating agents trigger a caspase‑independent, inflammatory necrosis that selectively kills glycolytic cancer cells through PARP‑mediated ATP loss, while cells dependent on oxidative phosphorylation resist this death.

Abstract

Necrosis has been considered a passive form of cell death in which the cell dies as a result of a bioenergetic catastrophe imposed by external conditions. However, in response to alkylating DNA damage, cells undergo necrosis as a self-determined cell fate. This form of death does not require the central apoptotic mediators p53, Bax/Bak, or caspases and actively induces an inflammatory response. Necrosis in response to DNA damage requires activation of the DNA repair protein poly(ADP-ribose) polymerase (PARP), but PARP activation is not sufficient to determine cell fate. Cell death is determined by the effect of PARP-mediated β-nicotinamide adenine dinucleotide (NAD) consumption on cellular metabolism. Cells using aerobic glycolysis to support their bioenergetics undergo rapid ATP depletion and death in response to PARP activation. In contrast, cells catabolizing nonglucose substrates to maintain oxidative phosphorylation are resistant to ATP depletion and death in response to PARP activation. Because most cancer cells maintain their ATP production through aerobic glycolysis, these data may explain the molecular basis by which DNA-damaging agents can selectively induce tumor cell death independent of p53 or Bcl-2 family proteins.