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Sci. Signal., 5 April 2011
Vol. 4, Issue 167, p. ra20
[DOI: 10.1126/scisignal.2000902]


Poly(ADP-Ribose) (PAR) Binding to Apoptosis-Inducing Factor Is Critical for PAR Polymerase-1–Dependent Cell Death (Parthanatos)

Yingfei Wang1,2, No Soo Kim1,2*, Jean-Francois Haince3, Ho Chul Kang1,2, Karen K. David1,2,4{dagger}, Shaida A. Andrabi1,2, Guy G. Poirier3, Valina L. Dawson1,2,4,5,6{ddagger}, and Ted M. Dawson1,2,4,5{ddagger}

1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, BRB 731, Baltimore, MD 21205, USA.
2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Health and Environment Unit, Laval University Medical Research Center, CHUQ, Ste-Foy, Quebec, Canada G1V 4G2.
4 Graduate Program in Cellular and Molecular Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
5 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* Present address: Brain Disease Research Center, Korea Institute of Oriental Medicine, 483 Expo-ro, Yuseong-gu, Daejeon 305-81, South Korea.

{dagger} Present address: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, PCTB 714, Baltimore, MD 21205, USA.

Abstract: The mitochondrial protein apoptosis-inducing factor (AIF) plays a pivotal role in poly(ADP-ribose) polymerase–1 (PARP-1)–mediated cell death (parthanatos), during which it is released from the mitochondria and translocates to the nucleus. We show that AIF is a high-affinity poly(ADP-ribose) (PAR)–binding protein and that PAR binding to AIF is required for parthanatos both in vitro and in vivo. AIF bound PAR at a site distinct from AIF’s DNA binding site, and this interaction triggered AIF release from the cytosolic side of the mitochondrial outer membrane. Mutation of the PAR binding site in AIF did not affect its NADH (reduced form of nicotinamide adenine dinucleotide) oxidase activity, its ability to bind FAD (flavin adenine dinucleotide) or DNA, or its ability to induce nuclear condensation. However, this AIF mutant was not released from mitochondria and did not translocate to the nucleus or mediate cell death after PARP-1 activation. These results suggest a mechanism for PARP-1 to initiate AIF-mediated cell death and indicate that AIF’s bioenergetic cell survival–promoting functions are separate from its effects as a mitochondrially derived death effector. Interference with the PAR-AIF interaction or PAR signaling may provide notable opportunities for preventing cell death after activation of PARP-1.

{ddagger} To whom correspondence should be addressed. E-mail: tdawson{at} (T.M.D.); vdawson{at} (V.L.D.)

Citation: Y. Wang, N. S. Kim, J.-F. Haince, H. C. Kang, K. K. David, S. A. Andrabi, G. G. Poirier, V. L. Dawson, T. M. Dawson, Poly(ADP-Ribose) (PAR) Binding to Apoptosis-Inducing Factor Is Critical for PAR Polymerase-1–Dependent Cell Death (Parthanatos). Sci. Signal. 4, ra20 (2011).

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