Critical Role of Poly(ADP-Ribose) Polymerase-1 in Modulating the Mode of Cell Death Caused by Continuous Oxidative Stress

Continuously generated hydrogen peroxide (H2O2) inhibits typical apoptosis and instead initiates a caspase-independent, apoptosis-inducing factor (AIF)-mediated pyknotic cell death. This may be related to H2O2-mediated DNA damage and subsequent ATP depletion, although the exact mechanisms by which the mode of cell death is decided after H2O2 exposure are still unclear. Accumulated evidence and our previous data led us to hypothesize that continuously generated H2O2, not an H2O2 bolus, induces severe DNA damage, signaling poly(ADP-ribose) polymerase-1 (PARP-1) activation, ATP depletion, and eventually caspase-independent cell death. Results from the present study support that H2O2 generated continuously by glucose oxidase causes excessive DNA damage and PARP-I activation. Blockage of PARP-1 by a siRNA transfection or by pharmacological inhibitor resulted in the significant inhibition of ATP depletion, loss of mitochondrial membrane potential, nuclear translocation of AIF and endonuclease G, and eventually conversion to caspase-dependent apoptosis. Overall, the current study demonstrates the different roles of PARP-I inhibition in modulation of cell death according to the method of H2O2 exposure, that is, continuous generation versus a direct addition. J. Cell.-Biochem. 108: 989-997, 2009. (C) 2009 Wiley-Liss, Inc.