title: A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1.
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.
authors.affiliation: 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.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology of Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Umanah
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Nambiar
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Eacker
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: BongWoo
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Maged M
authors.initials: MM
authors.lastname: Harraz
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Chang
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Wang
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jun Seop
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Neifert
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: 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.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: 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.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000201:enzymology; D002843:Chromatin / Q000378:metabolism; D053837:DNA Cleavage; D004249:DNA Damage / Q000235:genetics; D053938:DNA Fragmentation; D004277:DNA, Single-Stranded / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D009474:Neurons / Q000201:enzymology; D009690:Nucleic Acid Conformation; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D020521:Stroke / Q000201:enzymology / Q000235:genetics
chemical_list: D051033:Apoptosis Inducing Factor; D002843:Chromatin; D004277:DNA, Single-Stranded; D008263:Macrophage Migration-Inhibitory Factors; D018698:Glutamic Acid; D000071137:Poly (ADP-Ribose) Polymerase-1; D003851:Deoxyribonucleases; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human