Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

doi:10.1073/pnas.0606528103

Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

*Institute for Cell Engineering, Departments of
^†Neurology,
^‖Neuroscience, and
^††Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
^¶Health and Environment Unit, Laval University Medical Research Center, Centre Hospitalier Universitaire de Quebec, Ste-Foy, QC, Canada G1V 4G2

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 28, 2006 (received for review July 31, 2006)

Abstract

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-1-dependent cell death.

Footnotes

**To whom correspondence may be addressed. E-mail: vdawson{at}jhmi.edu or tdawson{at}jhmi.edu
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.
↵ ^‡Present address: Department of Neurology, Pharmacology and Toxicology, B-436 Life Science Building, Michigan State University, East Lansing, MI 48824.
↵ ^§Present address: Medical Biotechnology Center, Room N355, UMBI Building, University of Maryland, 725 West Lombard Street, Baltimore, MD 21201.
The authors declare no conflict of interest.
This article is a PNAS direct submission.