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

Author:

Yu Seong-Woon1,Wang Hongmin1,Poitras Marc F.1,Coombs Carmen1,Bowers William J.2,Federoff Howard J.2,Poirier Guy G.3,Dawson Ted M.145,Dawson Valina L.1465

Affiliation:

1. Departments of Neurology,

2. Department of Neurology, Center for Aging and Developmental Biology, University of Rochester, NY 14642, USA.

3. Health and Environment Unit, Laval University Medical Research Center, CHUQ, Ste-Foy, Quebec G1V 4G2, Canada.

4. Neuroscience, and

5. the Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

6. Physiology; and

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, H 2 O 2 , 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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