title: Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G.
abstract: Endonuclease G (EndoG) is a mitochondrial protein that is released from mitochondria and relocated into the nucleus to promote chromosomal DNA fragmentation during apoptosis. Here, we show that oxidative stress causes cell-death defects in C. elegans through an EndoG-mediated cell-death pathway. In response to high reactive oxygen species (ROS) levels, homodimeric CPS-6-the C. elegans homolog of EndoG-is dissociated into monomers with diminished nuclease activity. Conversely, the nuclease activity of CPS-6 is enhanced, and its dimeric structure is stabilized by its interaction with the worm AIF homolog, WAH-1, which shifts to disulfide cross-linked dimers under high ROS levels. CPS-6 thus acts as a ROS sensor to regulate the life and death of cells. Modulation of the EndoG dimer conformation could present an avenue for prevention and treatment of diseases resulting from oxidative stress.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC.
authors.forename: Jason L J
authors.initials: JLJ
authors.lastname: Lin
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Riley
authors.initials: R
authors.lastname: Skeen-Gaar
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC.
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Yang
authors.affiliation: School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhao
authors.affiliation: School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo 162-8666, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 162-8666, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA; School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China. Electronic address: ding.xue@colorado.edu.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC; Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University, Taiwan 10048, ROC. Electronic address: hanna@sinica.edu.tw.
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015536:Down-Regulation; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D029742:Caenorhabditis elegans Proteins; C469544:Cps-6 protein, C elegans; D024101:Mitochondrial Proteins; C469543:Wah-1 protein, C elegans; D004706:Endodeoxyribonucleases; C052391:endonuclease G
keywords: apoptosis; crystal structure; endonuclease G; mitochondria dysfunction; nuclease