Genes Dev. 27, 1089–1100 (2013)

Credit: JENNIFER JORDAN & DRAGONY FU

ALKBH7 is a mammalian homolog to the bacterial AlkB dioxygenase that repairs alkylated DNA, but it lacks detectable DNA repair activity, so its biological function remains unknown. Fu et al. show that stable genetic knockdown of ALKBH7 confers resistance to cell death in response to DNA-damaging agents. Overexpression of ALKBH7 restored sensitivity and necrotic cell death to ALKBH7-depeleted cells. However, in distinct cell lines, ALKBH7 depletion did not confer protection against apoptosis, indicating that ALKBH7 depletion is specifically protective against necrotic death. In cells that would normally undergo necrosis, DNA-damaging agents induced a short-lived drop in ATP and NAD+ when ALKBH7 was depleted, indicative of transient hyperactivation of PARP, an enzyme activated both in response to DNA damage and during necrosis. Supplementation with NAD+ or application of PARP inhibitors blocked necrosis, whereas small-molecule inhibitors of the NAD+ salvage pathway restored necrosis to ALKBH7-depleted cells. These experiments indicate that ALKBH7 disrupts cellular bioenergetics and may therefore affect mitochondrial function. Additional experiments indicated that blockade of mitochondrial respiration (but not glycolysis) disrupted ALKBH7-dependent necrosis. Although the precise activity of ALKBH7 in necrotic cell death remains to be determined, these studies indicate that selective activation of ALKBH7 might complement DNA-damaging chemotherapeutic agents to promote tumor cell death.