Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis

Genes Dev. 2013 May 15;27(10):1089-100. doi: 10.1101/gad.215533.113. Epub 2013 May 10.


Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.

Keywords: ALKBH7; AlkB; DNA damage; death; necrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • AlkB Enzymes
  • Alkylation
  • Apoptosis* / drug effects
  • Cell Line
  • DNA Damage* / drug effects
  • Drug Resistance
  • Energy Metabolism
  • Enzyme Activation
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / metabolism*
  • NAD / metabolism
  • Necrosis / metabolism
  • Necrosis / pathology
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Oxidation-Reduction
  • Oxidative Stress*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Transport


  • Mitochondrial Proteins
  • Nuclear Proteins
  • NAD
  • Adenosine Triphosphate
  • ALKBH7 protein, human
  • AlkB Enzymes
  • Poly(ADP-ribose) Polymerases