Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation

A hallmark of apoptosis is the fragmentation of nuclear DNA. Although this activity involves the caspase-3-dependent DNAse CAD (caspase-activated DNAse), evidence exists that DNA fragmentation can occur independently of caspase activity. Here we report on the ability of truncated Bid (tBid) to induce the release of a DNAse activity from mitochondria. This DNAse activity was identified by mass spectrometry as endonuclease G, an abundant 30 kDa protein released from mitochondria under apoptotic conditions. No tBid-induced endonuclease G release could be observed in mitochondria from Bcl-2-transgenic mice. The in vivo occurrence of endonuclease G release from mitochondria during apoptosis was confirmed in the liver from mice injected with agonistic anti-Fas antibody and is completely prevented in Bcl-2 transgenic mice. These data indicate that endonuclease G may be involved in CAD-independent DNA fragmentation during cell death pathways in which truncated Bid is generated. Cell Death and Differentiation (2001) 8, 1136–1142

[1]  B. Zhivotovsky,et al.  Review: nuclear events in apoptosis. , 2000, Journal of structural biology.

[2]  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.

[3]  N. Imamoto,et al.  Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation , 1999, Nature.

[4]  K. Yamamura,et al.  An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. , 2000, Genes & development.

[5]  Tak W. Mak,et al.  Two Distinct Pathways Leading to Nuclear Apoptosis , 2000, The Journal of experimental medicine.

[6]  John Calvin Reed,et al.  A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection , 1996, The Journal of experimental medicine.

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

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

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

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

[11]  D. Green,et al.  Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax , 2000, The Journal of experimental medicine.

[12]  W. Fiers,et al.  Cathepsin B-mediated activation of the proinflammatory caspase-11. , 1998, Biochemical and biophysical research communications.

[13]  C. Borner,et al.  Apoptosis without caspases: an inefficient molecular guillotine? , 1999, Cell Death and Differentiation.

[14]  W. Fiers,et al.  Molecular cloning and identification of murine caspase-8. , 1998, Journal of molecular biology.

[15]  L. Ellerby,et al.  Lysosomal Protease Pathways to Apoptosis , 2001, The Journal of Biological Chemistry.

[16]  K. Gevaert,et al.  A peptide concentration and purification method for protein characterization in the subpicomole range using matrix assisted laser desorption/ionization‐postsource decay (MALDI‐PSD) sequencing , 1998, Electrophoresis.

[17]  Ruedi Aebersold,et al.  Molecular characterization of mitochondrial apoptosis-inducing factor , 1999, Nature.

[18]  N. Copeland,et al.  Structure and promoter analysis of murine CAD and ICAD genes , 1999, Cell Death and Differentiation.

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

[20]  Xiaodong Wang,et al.  Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors , 1998, Cell.

[21]  A. Poustka,et al.  Functional characterization of DNase X, a novel endonuclease expressed in muscle cells. , 2000, Biochemistry.

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

[23]  Junying Yuan,et al.  Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis , 1998, Cell.