To die or to live: the dual role of poly(ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage.
Poly(ADP-ribose) polymerase-1 (PARP-1), activated by DNA strand breaks, participates in the DNA repair process physiologically. Excessive activation of PARP-1 mediates necrotic cell death under the status of oxidative stress and DNA damage. However, it remains elusive whether and how PARP-1 activation is involved in autophagy and what is the function of PARP-1-mediated autophagy under oxidative stress and DNA damage. We recently demonstrated that hydrogen peroxide (H(2)O(2)) induces autophagy through a novel autophagy signaling mechanism linking PARP-1 activation to the LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway. Furthermore, PARP-1-mediated autophagy plays a cytoprotective role in H(2)O(2)-induced necrotic cell death as suppression of autophagy greatly sensitizes H2O2- induced cell death. Our study thus identifies a novel function of PARP-1 in mediating autophagy and it appears that PAPR-1 possesses a dual role in modulating necrosis and autophagy under oxidative stress and DNA damage: on the one hand, overactivation of PARP-1 leads to ATP depletion and necrotic cell death; on the other hand, PARP-1 activation promotes autophagy via the LKB1- AMPK-mTOR pathway to enhance cell survival. The cellular decision of life or death depends on the balance between autophagy and necrosis mediated by these two distinct pathways.
Huang
Qing
Q
Department of Community, Occupational & Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Shen
Han-Ming
HM
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009336:Necrosis / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases