Apoptosis-Inducing Factor Mediates Poly(ADP-Ribose) (PAR) Polymer-Induced Cell Death

Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation. How PARP-1 activation leads to AIF release is not known. Here we identify PAR polymer as a cell death signal th...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 103; no. 48; pp. 18314 - 18319
Main Authors Yu, Seong-Woon, Andrabi, Shaida A., Wang, Hongmin, Kim, No Soo, Poirier, Guy G., Dawson, Ted M., Dawson, Valina L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.11.2006
National Acad Sciences
Subjects
Animals
Antibodies
Apoptosis Inducing Factor - metabolism
Biological Sciences
Cell death
Cell Death - drug effects
Cell Nucleus - drug effects
Cells, Cultured
Condensation
Cytosol - drug effects
Fractionation
HeLa cells
Histones
Humans
Mice
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
N methyl D aspartate receptors
Neurons
Neurons - drug effects
Neurons - metabolism
Poly Adenosine Diphosphate Ribose - pharmacology
Polymers
Polymers - pharmacology
Protein Transport
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Summary:Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation. How PARP-1 activation leads to AIF release is not known. Here we identify PAR polymer as a cell death signal that induces release of AIF. PAR polymer induces mitochondrial AIF release and translocation to the nucleus. PAR glycohydrolase, which degrades PAR polymer, prevents PARP-1-dependent AIF release. Cells with reduced levels of AIF are resistant to PARP-1-dependent cell death and PAR polymer cytotoxicity. These results reveal PAR polymer as an AIF-releasing factor that plays important roles in PARP-1dependent cell death.
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Present address: Medical Biotechnology Center, Room N355, UMBI Building, University of Maryland, 725 West Lombard Street, Baltimore, MD 21201.
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 28, 2006
Present address: Department of Neurology, Pharmacology and Toxicology, B-436 Life Science Building, Michigan State University, East Lansing, MI 48824.
Author contributions: S.-W.Y. and S.A.A. contributed equally to this work; T.M.D. and V.L.D. contributed equally to this work; S.-W.Y., S.A.A., H.W., N.S.K., G.G.P., T.M.D., and V.L.D. designed research; S.-W.Y., S.A.A., H.W., and N.S.K. performed research; G.G.P. contributed new reagents/analytic tools; S.-W.Y., S.A.A., H.W., N.S.K., T.M.D., and V.L.D. analyzed data; and S.-W.Y., S.A.A., T.M.D., and V.L.D. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0606528103