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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89 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 languageEnglish (US)
Article numberaad6872
JournalScience
Volume354
Issue number6308
DOIs
StatePublished - 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), [aad6872]. https://doi.org/10.1126/science.aad6872