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Mediation of Poly(ADP-Ribose) Polymerase-1-Dependent Cell Death by Apoptosis-Inducing Factor

Seong-Woon Yu, Hongmin Wang, Marc F. Poitras, Carmen Coombs, William J. Bowers, Howard J. Federoff, Guy G. Poirier, Ted M. Dawson and Valina L. Dawson
Science
Vol. 297, No. 5579 (Jul. 12, 2002), pp. 259-263
Stable URL: http://www.jstor.org/stable/3077061
Page Count: 5
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Mediation of Poly(ADP-Ribose) Polymerase-1-Dependent Cell Death by Apoptosis-Inducing Factor
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Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N′-nitro-N-nitrosoguanidine, H2O2, and N-methyl-D-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

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