EndoG is dispensable in embryogenesis and apoptosis

The mitochondrial protein, endonuclease G (EndoG), is one of the endonucleases implicated in DNA fragmentation during apoptosis. It has been shown to translocate from the mitochondria to the nucleus upon cell death stimuli. These observations suggest that EndoG is a mitochondrial cell death effector, and that it possibly acts as a cell death nuclease, similar to DNA fragmentation factor. To better understand the role of EndoG in development and apoptosis, we generated EndoG null mice by homologous gene targeting without disruption of D2Wsu81e. EndoG null mice are viable and develop to adulthood with no obvious abnormalities. Fibroblasts generated from the EndoG null mice show no difference in susceptibility when induced to die by a variety of intrinsic and extrinsic apoptotic stimuli. Additionally, EndoG null mice are equally sensitive to excitotoxic stress. These data suggest that EndoG is not essential for early embryogenesis and apoptosis.

[1]  J. Eppig,et al.  Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome. , 1998, Human molecular genetics.

[2]  N. Hamasaki,et al.  Mammalian mitochondrial endonuclease G. Digestion of R-loops and localization in intermembrane space. , 2002, European journal of biochemistry.

[3]  B. Martinac,et al.  Mechanisms of AIF-Mediated Apoptotic DNA Degradation in Caenorhabditis elegans , 2002 .

[4]  N. Osheroff,et al.  Topoisomerase II·Etoposide Interactions Direct the Formation of Drug-induced Enzyme-DNA Cleavage Complexes* , 1996, The Journal of Biological Chemistry.

[5]  M. Gerschenson,et al.  Mitochondrial endonuclease activity in the rat varies markedly among tissues in relation to the rate of tissue metabolism. , 1991, Biochimica et biophysica acta.

[6]  J. Eppig,et al.  Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. , 2000, Development.

[7]  S. Lipton,et al.  BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. , 2004, Molecular cell.

[8]  Lily Y. Li,et al.  Action of Recombinant Human Apoptotic Endonuclease G on Naked DNA and Chromatin Substrates , 2001, The Journal of Biological Chemistry.

[9]  H. P. Zassenhaus,et al.  Construction of a yeast mutant lacking the mitochondrial nuclease. , 1988, Nucleic acids research.

[10]  Eve DakeS,et al.  Purification and properties of the major nuclease from mitochondria of Saccharomyces cerevisiae. , 1988, The Journal of biological chemistry.

[11]  B. Aggarwal.  Signalling pathways of the TNF superfamily: a double-edged sword , 2003, Nature Reviews Immunology.

[12]  J. Hoek,et al.  A Ca2+-induced mitochondrial permeability transition causes complete release of rat liver endonuclease G activity from its exclusive location within the mitochondrial intermembrane space. Identification of a novel endo-exonuclease activity residing within the mitochondrial matrix. , 2003, Nucleic acids research.

[13]  S. Nagata,et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD , 1998, Nature.

[14]  R. V. Tigerstrom.  Purification and characteristics of a mitochondrial endonuclease from the yeast Saccharomyces cerevisiae. , 1982 .

[15]  Jay Z. Parrish,et al.  Mitochondrial endonuclease G is important for apoptosis in C. elegans , 2001, Nature.

[16]  Jay Z. Parrish,et al.  Functional genomic analysis of apoptotic DNA degradation in C. elegans. , 2003, Molecular cell.

[17]  S. Orrenius,et al.  The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells. , 1982, The Journal of biological chemistry.

[18]  G. Denniger,et al.  Analysis of the role of the NUC1 endo/exonuclease in yeast mitochondrial DNA recombination , 1994, Current Genetics.

[19]  Xiaodong Wang,et al.  DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis , 1997, Cell.

[20]  T. Dawson,et al.  Mediation of Poly(ADP-Ribose) Polymerase-1-Dependent Cell Death by Apoptosis-Inducing Factor , 2002, Science.

[21]  J. Cote,et al.  Primers for mitochondrial DNA replication generated by endonuclease G. , 1993, Science.

[22]  A. Roulston,et al.  CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45 , 1998, Current Biology.

[23]  D. Guastella,et al.  NMDA But Not Non-NMDA Excitotoxicity is Mediated by Poly(ADP-Ribose) Polymerase , 2000, The Journal of Neuroscience.

[24]  A. Gescher.  Staurosporine analogues - pharmacological toys or useful antitumour agents? , 2000, Critical reviews in oncology/hematology.

[25]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[26]  Xiaodong Wang,et al.  Endonuclease G is required for early embryogenesis and normal apoptosis in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Xu Luo,et al.  Endonuclease G is an apoptotic DNase when released from mitochondria , 2001, Nature.

[28]  L. Kaer,et al.  Resistance to DNA fragmentation and chromatin condensation in mice lacking the DNA fragmentation factor 45. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  坂平 英樹.  Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis , 2000 .

[30]  F. Cecconi,et al.  Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak‐mediated permeabilization , 2003, The EMBO journal.

[31]  Z. Siddik,et al.  Cisplatin: mode of cytotoxic action and molecular basis of resistance , 2003, Oncogene.

[32]  S. Ikeda,et al.  Action of mitochondrial endonuclease G on DNA damaged by L-ascorbic acid, peplomycin, and cis-diamminedichloroplatinum (II). , 1997, Biochemical and biophysical research communications.

[33]  D. Newmeyer,et al.  Mitochondrial Release of Pro-apoptotic Proteins , 2005, Journal of Biological Chemistry.

[34]  J. Rosamond.  Purification and properties of an endonuclease from the mitochondrion of Saccharomyces cerevisiae. , 1981, European journal of biochemistry.

[35]  B. de Kruijff,et al.  Improved methods to isolate and subfractionate rat liver mitochondria. Lipid composition of the inner and outer membrane. , 1990, Biochimica et biophysica acta.

[36]  P. Vandenabeele,et al.  Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation , 2001, Cell Death and Differentiation.

[37]  M. Lieber,et al.  Generation and Characterization of Endonuclease G Null Mice , 2005, Molecular and Cellular Biology.