@article{c55fefb0e09841508e20626a3c97aa12,
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.",
author = "Yingfei Wang and Ran An and Umanah, {George K.} and Hyejin Park and Kalyani Nambiar and Eacker, {Stephen M.} and Bongwoo Kim and Lei Bao and Harraz, {Maged M.} and Calvin Chang and Rong Chen and Wang, {Jennifer E.} and Kam, {Tae In} and Jeong, {Jun Seop} and Zhi Xie and Stewart Neifert and Jiang Qian and Andrabi, {Shaida A.} and Seth Blackshaw and Heng Zhu and Hongjun Song and Ming, {Guo Li} and Dawson, {Valina L.} and Dawson, {Ted M.}",
note = "Funding Information: This work was supported by NIH grant K99/R00 NS078049, American Heart Association (AHA) National Scientist Development Grant 12SDG11900071, and the University of Texas Southwestern Medical Center Department of Pathology Startup funds and UT Rising Stars to Y.W.; and grants from National Institute on Drug Abuse, NIH, DA000266; and National Institute of Neurological Disorders and Stroke, NIH, R01 NS067525, R37 NS067525, and NS38377 to T.M.D. and V.L.D. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the foundation's Parkinson's Disease Program M-2016. ChIP-seq data are archived in National Center for Biotechnology Information, NIH, GEO, GSE65110. Y.W. contributed to all aspects of the project. R.A., G.K.U., K.N., H.P., B.K., L.B., M.M.H., C.C., R.C., S.M.E., M.M.H., T.-I.K., S.N., G.M., and H.S. helped with some experiments. J.S.J., S.B., and H.Z. provided protein chips. Z.X. and J.Q. helped with the bioinformatics analysis. Y.W., V.L.D., and T.M.D. designed experiments and wrote the paper. The study was conceived and scientifically directed by V.L.D. and T.M.D. Y.W., H.P., V.L.D., and T.M.D. are inventors on a patent application submitted by Johns Hopkins University that covers the use of inhibitors of MIF nuclease activity to treat stroke and other disorders. The supplementary materials contain additional data. Publisher Copyright: {\textcopyright} 2016, American Association for the Advancement of Science. All rights reserved.",
year = "2016",
month = oct,
day = "7",
doi = "10.1126/science.aad6872",
language = "English (US)",
volume = "354",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6308",
}