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Nature 391, 43-50 (1 January 1998) | doi:10.1038/34112; Received 19 November 1997; Accepted 1 December 1997

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

Masato Enari1, Hideki Sakahira1, Hideki Yokoyama1, Katsuya Okawa2, Akihiro Iwamatsu2 & Shigekazu Nagata1,3

  1. Department of Genetics, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan
  2. Central Laboratories for Key Technology, Kirin Brewery Co., 1-13-5 Fukuura, Kanazawa, Yokohama, Kanagawa 236, Japan
  3. Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565, Japan

Correspondence to: Shigekazu Nagata1,3 Correspondence and requests for materials should be addressed to S.N. (e-mail: Email: nagata@genetic.med.osaka-u.ac.jp). The nucleotide sequence data will appear in the DDBJ, EMBL and

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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.

  1. Department of Genetics, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan
  2. Central Laboratories for Key Technology, Kirin Brewery Co., 1-13-5 Fukuura, Kanazawa, Yokohama, Kanagawa 236, Japan
  3. Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565, Japan

Correspondence to: Shigekazu Nagata1,3 Correspondence and requests for materials should be addressed to S.N. (e-mail: Email: nagata@genetic.med.osaka-u.ac.jp). The nucleotide sequence data will appear in the DDBJ, EMBL and