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

Yingfei Wang; Ran An; George K Umanah; Hyejin Park; Kalyani Nambiar; Stephen M Eacker; BongWoo Kim; Lei Bao; Maged M Harraz; Calvin Chang; Rong Chen; Jennifer E Wang; Tae-In Kam; Jun Seop Jeong; Zhi Xie; Stewart Neifert; Jiang Qian; Shaida A Andrabi; Seth Blackshaw; Heng Zhu; Hongjun Song; Guo-Li Ming; Valina L Dawson; Ted M Dawson

doi:10.1126/science.aad6872

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

Science. 2016 Oct 7;354(6308):aad6872. doi: 10.1126/science.aad6872.

Authors

Yingfei Wang^{1

2

3

4}, Ran An^{5

2

6}, George K Umanah^{5

2}, Hyejin Park^{5

2

7}, Kalyani Nambiar^{5

2}, Stephen M Eacker^{5

2

7}, BongWoo Kim³, Lei Bao³, Maged M Harraz^{5

2

8}, Calvin Chang⁵, Rong Chen^{5

2}, Jennifer E Wang³, Tae-In Kam^{5

2

7}, Jun Seop Jeong^{9

10}, Zhi Xie¹¹, Stewart Neifert^{5

2

7}, Jiang Qian¹¹, Shaida A Andrabi^{5

2}, Seth Blackshaw^{8

10

11}, Heng Zhu^{9

10}, Hongjun Song^{5

2

8}, Guo-Li Ming^{5

2

8}, Valina L Dawson^{1

2

7

8

12}, Ted M Dawson^{1

2

7

8

9}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. [email protected] [email protected] [email protected].
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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Active Transport, Cell Nucleus
Amino Acid Sequence
Animals
Apoptosis Inducing Factor / genetics
Apoptosis Inducing Factor / metabolism*
Apoptosis* / genetics
Base Sequence
Catalytic Domain
Cell Nucleus / enzymology
Chromatin / metabolism
DNA Cleavage*
DNA Damage* / genetics
DNA Fragmentation
DNA, Single-Stranded / metabolism*
Deoxyribonucleases / chemistry
Deoxyribonucleases / genetics
Deoxyribonucleases / metabolism*
Glutamic Acid / chemistry
Glutamic Acid / genetics
Glutamic Acid / toxicity
HeLa Cells
Humans
Intramolecular Oxidoreductases / chemistry
Intramolecular Oxidoreductases / genetics
Intramolecular Oxidoreductases / metabolism*
Macrophage Migration-Inhibitory Factors / chemistry
Macrophage Migration-Inhibitory Factors / genetics
Macrophage Migration-Inhibitory Factors / metabolism*
Mice
Mice, Knockout
Mitochondria / enzymology
Mutation
Neurons / enzymology
Nucleic Acid Conformation
Oxidative Stress
Poly (ADP-Ribose) Polymerase-1 / metabolism*
Stroke / enzymology
Stroke / genetics

Substances

Apoptosis Inducing Factor
Chromatin
DNA, Single-Stranded
Macrophage Migration-Inhibitory Factors
Glutamic Acid
Poly (ADP-Ribose) Polymerase-1
Deoxyribonucleases
Intramolecular Oxidoreductases
MIF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding