Journal Article

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

Eacker, Stephen M., Nambiar, Kalyani, Harraz, Maged M., Umanah, George K., Bao, Lei, Jeong, Jun Seop, Neifert, Stewart, Kim, BongWoo, Dawson, Valina L., Ming, Guo-li, Kam, Tae-In, Wang, Yingfei, Zhu, Heng, Chen, Rong, Park, Hyejin, Dawson, Ted M., Wang, Jennifer E., Andrabi, Shaida A., Blackshaw, Seth, Chang, Calvin, Xie, Zhi, An, Ran, Qian, Jiang, Song, Hongjun

2016

Overview

Cells that experience stresses and accumulate excessive damage to DNA undergo cell death mediated by a nuclear enzyme known as PARP-1. During this process, apoptosis-inducing factor (AIF) translocates to the nucleus and activates one or more nucleases to cleave DNA. Wang et al. found that macrophage migration inhibitory factor (MIF) is an AIF-associated endonuclease that contributes to PARP-1-induced DNA fragmentation (see the Perspective by Jonas). In mouse neurons in culture, loss of MIF protected neurons from cell death caused by excessive stimulation. Targeting MIF could thus provide a therapeutic strategy against diseases in which PARP-1 activation is excessive. Science , this issue p. 82 ; see also p. 36 An endonuclease that functions in a disease-associated form of cell death is identified. [Also see Perspective by Jonas ] 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Activation / Active Transport, Cell Nucleus / Adenosine diphosphate / Amino Acid Sequence / Amino acids / Animals / Apoptosis - genetics / Apoptosis Inducing Factor - genetics / Apoptosis Inducing Factor - metabolism / Base Sequence / Catalytic Domain / Cell death / Cell Nucleus - enzymology / Cells / Chromatin - metabolism / Damage accumulation / Deoxyribonucleases - chemistry / Deoxyribonucleases - genetics / Deoxyribonucleases - metabolism / Deoxyribonucleic acid / Diseases / DNA / DNA Cleavage / DNA damage / DNA Damage - genetics / DNA Fragmentation / DNA, Single-Stranded - metabolism / Genetics / Genomics / Glutamic Acid - chemistry / Glutamic Acid - genetics / Glutamic Acid - toxicity / HeLa Cells / Humans / Inhibition / Injuries / Intramolecular Oxidoreductases - chemistry / Intramolecular Oxidoreductases - genetics / Intramolecular Oxidoreductases - metabolism / Macrophage Migration-Inhibitory Factors - chemistry / Macrophage Migration-Inhibitory Factors - genetics / Macrophage Migration-Inhibitory Factors - metabolism / Mice / Mice, Knockout / Migration / Mitochondria - enzymology / Mortality / Mutation / Myocardial infarction / Neurons - enzymology / Nuclease / Nuclei / Nucleic Acid Conformation / Oxidative Stress / Poly (ADP-Ribose) Polymerase-1 - metabolism / Polymerase chain reaction / RESEARCH ARTICLE SUMMARY / Stroke - enzymology / Stroke - genetics / Topology / Translocation