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

Yingfei Wang(Johns Hopkins University), Ran An(Johns Hopkins University), George K. E. Umanah(Johns Hopkins University), Hyejin Park(Johns Hopkins University), Kalyani Nambiar(Johns Hopkins University), Stephen Eacker(Johns Hopkins University), BongWoo Kim(The University of Texas Southwestern Medical Center), Lei Bao(The University of Texas Southwestern Medical Center), Maged M. Harraz(Johns Hopkins University), Calvin Chang(Johns Hopkins University), Rong Chen(Johns Hopkins University), Jennifer E. Wang(The University of Texas Southwestern Medical Center), Tae‐In Kam(Johns Hopkins University), Jun Seop Jeong(Johns Hopkins University), Zhi Xie(Johns Hopkins University), Stewart Neifert(Johns Hopkins University), Jiang Qian(Johns Hopkins University), Shaida A. Andrabi(Johns Hopkins University), Seth Blackshaw(Johns Hopkins University), Heng Zhu(Johns Hopkins University), Hongjun Song(Johns Hopkins University), Guo‐li Ming(Johns Hopkins University), Valina L. Dawson(Johns Hopkins University), Ted M. Dawson(Johns Hopkins University)
Science
October 6, 2016
10.1126/science.aad6872
Cited by 407

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.

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