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Science. 2016 Oct 7;354(6308). pii: aad6872.

A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1.

Wang Y1,2,3,4, An R5,2,6, Umanah GK5,2, Park H5,2,7, Nambiar K5,2, Eacker SM5,2,7, Kim B3, Bao L3, Harraz MM5,2,8, Chang C5, Chen R5,2, Wang JE3, Kam TI5,2,7, Jeong JS9,10, Xie Z11, Neifert S5,2,7, Qian J11, Andrabi SA5,2, Blackshaw S8,10,11, Zhu H9,10, Song H5,2,8, Ming GL5,2,8, Dawson VL1,2,7,8,12, Dawson TM1,2,7,8,9.

Author information

1
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu vdawson1@jhmi.edu yingfei.wang@utsouthwestern.edu.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Department of Neurology of Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
7
Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
8
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

Inhibition or genetic deletion of poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is protective against toxic insults in many organ systems. The molecular mechanisms underlying PARP-1-dependent cell death involve release of mitochondrial apoptosis-inducing factor (AIF) and its translocation to the nucleus, which results in chromatinolysis. We identified macrophage migration inhibitory factor (MIF) as a PARP-1-dependent AIF-associated nuclease (PAAN). AIF was required for recruitment of MIF to the nucleus, where MIF cleaves genomic DNA into large fragments. Depletion of MIF, disruption of the AIF-MIF interaction, or mutation of glutamic acid at position 22 in the catalytic nuclease domain blocked MIF nuclease activity and inhibited chromatinolysis, cell death induced by glutamate excitotoxicity, and focal stroke. Inhibition of MIF's nuclease activity is a potential therapeutic target for diseases caused by excessive PARP-1 activation.

Comment in

PMID:
27846469
PMCID:
PMC5134926
DOI:
10.1126/science.aad6872
[Indexed for MEDLINE]
Free PMC Article

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