c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation

Reactive oxygen species ( ROS) have been closely associated with both apoptotic and non- apoptotic/ necrotic cell death. Our previous study has illustrated that c- Jun- N- terminal kinase 1 ( JNK1) is the main executor in hydrogen peroxide ( H2O2)- induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H2O2- induced cell death. In this study, poly( ADP- ribose) polymerase- 1 ( PARP- 1), a key DNA repair protein, was readily activated by H2O2 and inhibition of PARP- 1 activation by either a pharmacological or genetic approach offered significant protection against H2O2- induced cell death. More importantly, H2O2- mediated PARP- 1 activation is subject to regulation by JNK1. Suppression of JNK1 activation by a chemical inhibitor or genetic deletion markedly suppressed the late- phase PARP- 1 activation induced by H2O2, suggesting that JNK1 contributes to the sustained activation of PARP- 1. Such findings were supported by the temporal pattern of nuclear translocation of activated JNK and a direct protein - protein interaction between JNK1 and PARP- 1 in H2O2- treated cells. Finally, in vitro kinase assay suggests that PARP- 1 may serve as the direct phosphorylation target for JNK1. Taken together, data from our study reveal a novel underlying mechanism in H2O2- induced nonapoptotic cell death: JNK1 promotes a sustained PARP- 1 activation via nuclear translocation, protein - protein interaction and PARP- 1 phosphorylation.