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Molecular and Cellular Biology, July 2007, p. 4844-4862, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02141-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sequential Activation of Poly(ADP-Ribose) Polymerase 1, Calpains, and Bax Is Essential in Apoptosis-Inducing Factor-Mediated Programmed Necrosis

Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur, Paris, France,¹ Queen's Cancer Research Institute, Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada,² Département Intégrité du génôme CNRS-UMR 7175, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France³

Received 15 November 2006/ Returned for modification 30 January 2007/ Accepted 16 April 2007

Alkylating DNA damage induces a necrotic type of programmed cell death through the poly(ADP-ribose) polymerases (PARP) and apoptosis-inducing factor (AIF). Following PARP activation, AIF is released from mitochondria and translocates to the nucleus, where it causes chromatin condensation and DNA fragmentation. By employing a large panel of gene knockout cells, we identified and describe here two essential molecular links between PARP and AIF: calpains and Bax. Alkylating DNA damage initiated a p53-independent form of death involving PARP-1 but not PARP-2. Once activated, PARP-1 mediated mitochondrial AIF release and necrosis through a mechanism requiring calpains but not cathepsins or caspases. Importantly, single ablation of the proapoptotic Bcl-2 family member Bax, but not Bak, prevented both AIF release and alkylating DNA damage-induced death. Thus, Bax is indispensable for this type of necrosis. Our data also revealed that Bcl-2 regulates N-methyl-N'-nitro-N'-nitrosoguanidine-induced necrosis. Finally, we established the molecular ordering of PARP-1, calpains, Bax, and AIF activation, and we showed that AIF downregulation confers resistance to alkylating DNA damage-induced necrosis. Our data shed new light on the mechanisms regulating AIF-dependent necrosis and support the notion that, like apoptosis, necrosis could be a highly regulated cell death program.

Published ahead of print on 30 April 2007.

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