| Literature DB >> 27846469 |
Yingfei Wang1,2,3,4, Ran An5,2,6, George K Umanah5,2, Hyejin Park5,2,7, Kalyani Nambiar5,2, Stephen M Eacker5,2,7, BongWoo Kim3, Lei Bao3, Maged M Harraz5,2,8, Calvin Chang5, Rong Chen5,2, Jennifer E Wang3, Tae-In Kam5,2,7, Jun Seop Jeong9,10, Zhi Xie11, Stewart Neifert5,2,7, Jiang Qian11, Shaida A Andrabi5,2, Seth Blackshaw8,10,11, Heng Zhu9,10, Hongjun Song5,2,8, Guo-Li Ming5,2,8, Valina L Dawson1,2,7,8,12, Ted M Dawson1,2,7,8,9.
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.Entities:
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Year: 2016 PMID： 27846469 PMCID： PMC5134926 DOI： 10.1126/science.aad6872
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728