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

Science  12 Jul 2002:
Vol. 297, Issue 5579, pp. 259-263
DOI: 10.1126/science.1072221

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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, andN-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.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: vdawson{at}jhmi.edu

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