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

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, m...

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Bibliographic Details
Published in:Genes & development 2013-05, Vol.27 (10), p.1089-1100
Main Authors: Fu, Dragony, Jordan, Jennifer J, Samson, Leona D
Format: Article
Language:English
Subjects:
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
Research Paper
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.215533.113