A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD

Nature. 1998 Jan 1;391(6662):43-50. doi: 10.1038/34112.

Abstract

The homeostasis of animals is regulated not only by the growth and differentiation of cells, but also by cell death through a process known as apoptosis. Apoptosis is mediated by members of the caspase family of proteases, and eventually causes the degradation of chromosomal DNA. A caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD) have now been identified in the cytoplasmic fraction of mouse lymphoma cells. CAD is a protein of 343 amino acids which carries a nuclear-localization signal; ICAD exists in a long and a short form. Recombinant ICAD specifically inhibits CAD-induced degradation of nuclear DNA and its DNase activity. When CAD is expressed with ICAD in COS cells or in a cell-free system, CAD is produced as a complex with ICAD: treatment with caspase 3 releases the DNase activity which causes DNA fragmentation in nuclei. ICAD therefore seems to function as a chaperone for CAD during its synthesis, remaining complexed with CAD to inhibit its DNase activity; caspases activated by apoptotic stimuli then cleave ICAD, allowing CAD to enter the nucleus and degrade chromosomal DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • COS Cells
  • Caspase 3
  • Caspases*
  • Cloning, Molecular
  • Cysteine Endopeptidases / metabolism
  • DNA / metabolism*
  • Deoxyribonucleases / antagonists & inhibitors
  • Deoxyribonucleases / isolation & purification
  • Deoxyribonucleases / metabolism*
  • Enzyme Activation
  • Enzyme Inhibitors
  • Escherichia coli
  • Humans
  • Mice
  • Molecular Sequence Data
  • Proteins / chemistry
  • Proteins / isolation & purification
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Tumor Cells, Cultured

Substances

  • Apoptosis Regulatory Proteins
  • DNA fragmentation factor, human
  • Enzyme Inhibitors
  • Proteins
  • Recombinant Fusion Proteins
  • caspase-activated DNase inhibitor
  • DNA
  • Deoxyribonucleases
  • caspase-activated deoxyribonuclease
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases

Associated data

  • GENBANK/AB009375
  • GENBANK/AB009376
  • GENBANK/AB009377