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

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 ZhuHongjun Song, Guo Li Ming, Valina L. Dawson, Ted M. Dawson

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256 Scopus citations

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.

Original language	English (US)
Article number	aad6872
Journal	Science
Volume	354
Issue number	6308
DOIs	https://doi.org/10.1126/science.aad6872
State	Published - Oct 7 2016

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Wang, Y., An, R., Umanah, G. K., Park, H., Nambiar, K., Eacker, S. M., Kim, B., Bao, L., Harraz, M. M., Chang, C., Chen, R., Wang, J. E., Kam, T. I., Jeong, J. S., Xie, Z., Neifert, S., Qian, J., Andrabi, S. A., Blackshaw, S., ... Dawson, T. M. (2016). A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science, 354(6308), Article aad6872. https://doi.org/10.1126/science.aad6872

Wang, Y, An, R, Umanah, GK, Park, H, Nambiar, K, Eacker, SM, Kim, B, Bao, L, Harraz, MM, Chang, C, Chen, R, Wang, JE, Kam, TI, Jeong, JS, Xie, Z, Neifert, S, Qian, J, Andrabi, SA, Blackshaw, S, Zhu, H, Song, H, Ming, GL, Dawson, VL & Dawson, TM 2016, 'A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1', Science, vol. 354, no. 6308, aad6872. https://doi.org/10.1126/science.aad6872

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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.}",

year = "2016",

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doi = "10.1126/science.aad6872",

language = "English (US)",

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AU - Wang, Yingfei

AU - An, Ran

AU - Umanah, George K.

AU - Park, Hyejin

AU - Nambiar, Kalyani

AU - Eacker, Stephen M.

AU - Kim, Bongwoo

AU - Bao, Lei

AU - Harraz, Maged M.

AU - Chang, Calvin

AU - Chen, Rong

AU - Wang, Jennifer E.

AU - Kam, Tae In

AU - Jeong, Jun Seop

AU - Xie, Zhi

AU - Neifert, Stewart

AU - Qian, Jiang

AU - Andrabi, Shaida A.

AU - Blackshaw, Seth

AU - Zhu, Heng

AU - Song, Hongjun

AU - Ming, Guo Li

AU - Dawson, Valina L.

AU - Dawson, Ted M.

PY - 2016/10/7

Y1 - 2016/10/7

N2 - 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.

AB - 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.

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

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