Deoxyribonuclease

Details Deoxyribonuclease Deoxyribonuclease

1996-05-06

1998-10-13

Wax, Robert A.

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

435240, 4352523, 4353201, 435325, 536 232, 935 22, C12N 922, C12N 100, C12N 120, C07H 2104

Patent

active

058211039

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to three kinds of novel deoxyribonucleases (hereinafter simply referred to as DNase). More particularly, the present invention relates to a novel DNase which catalyzes the fragmentation of DNA, that is, digestion of chromatin DNA into mono- or oligonucleosome units, which is a characteristic phenomenon in apoptosis.
The present invention also relates to a DNA encoding the amino acid sequence of one (DNase .gamma. to be mentioned later) of the above-mentioned novel DNases, a vector containing said DNA, a host cell transformed with said vector, production of said DNase, which comprises culture of said host cell, and to an antibody having affinity for said DNase, a precursor polypeptide thereof or a fragment thereof.


BACKGROUND ART

Apoptosis has recently been attracting attention with regard to the death of cells or tissues. Unlike pathologic death of cells (necrosis), apoptosis is considered to be the death programmed in the gene of cells from the beginning. That is, certain external or internal factors trigger to activate the genes which program apoptosis and the active death is brought to the cell as a result of the activation of this self-destructive program.


TABLE 1 ______________________________________ Phenomena of apoptosis ______________________________________ developmental stage morphogenesis, metamorphosis, establishment of nervous system alternation of normal hemocyte, epidermal cells, epithelial cells cells of small intestine and stomach nervous system death of neurons due to the removal of neurotrophic factors endocrine death of thymocytes by glucocorticoid atrophy of prostate by androgen removal immune system death of autoimmune cells death of tumor cells by cytotoxic T lymphocytes irradiation death of thymocytes highly sensitive to irradiation viral infection cell death by infection with AIDS or influenza virus cancer death of tumor cells in malignant tissues drug, poison cell death by antitumor agents or bacterial toxins heat death of tumor cells by thermotherapy ______________________________________
As shown in Table 1 above, apoptosis is involved in a great number of vital phenomena. It is suggested that apoptosis is responsible for not only morphogenesis during developmental stages, but also alternation of normal cells (removal of old cells), such as epidermal cells of skin and epithelial cells of small intestine and stomach of mature individuals, atrophy of hormone-dependent tissue thymus by glucocorticoid, atrophy of prostate by castration, elimination of immunocompetent cells which react with self-components, and death of neurons due to the removal of neurotrophic factors.
In addition to such physiological death of cells, apoptosis is also found in the death of cells exposed to irradiation and virus-infected cells. A decrease in T lymphocytes due to AIDS virus has been reported to be also caused by apoptosis, which attracted much attention. Besides these, apoptosis is caused by chemical or physical stimulation, such as administration of medications and poisonous substances, and heat. The death of neurons in neurodegenerative diseases such as Alzheimer's disease, and natural apoptosis of tumor cells and cell death by antitumor agents which occur in malignant tumor lesion have been found to be caused by apoptosis.
Thus, elucidation of molecular mechanisms of apoptosis is crucial for the understanding of biochemical significance and role of cell death in ontogenesis and suppression of carcinogenesis.
The characteristic phenomena commonly observed in apoptosis are morphological changes such as contraction of cell along with the changes in cell membrane (elimination of microbilli) and condensation of (1972), Nature 284, 555-556 (1980)!. In particular, fragmentation of chromatin DNA into nucleosomal units (FIG. 1) is the most noticeable phenomenon commonly seen in every apoptotic cell, irrespective of the diversity of causative factors of apoptosis, which suggests that apoptosis cascade e

REFERENCES:
Shiokawa et al., Endonuclease in apoptosis Experimental Medicine, vol. 11, No. 17, Tokyo (1993) pp. 2370-2375.
Tanuma et al., Multiple Forms of Nuclear Deoxyribonuclease in Rat Thymocytes, Biochemical And Biophysical Research Communications, vol. 203, No. 2 pp. 789-797 (Sept. 15, 1994).
Kreuder et al. (1984) Isolation, characterization and cyrstallization of deoxyribonuclease I from bovine and rat parotid gland and its interaction with rabbit skeletal muscle actin. Eur. J. Biochem. 139:389-400, Feb. 1984.
Polzar et al. (1990) Nucleotide sequence of a full length cDNA clone encoding the deoxyribonuclease I from rat parotid gland. Nucleic Acids Research 18 (23):7151, Dec. 11, 1919.
Ishida et al. (1974) Isolation and Purification of Clacium and Magnesium Dependent Endonuclease from Rat Liver Nuclei. Biochem. Biophys. Res. Commun. 56 (3):703-710, Apr. 1974.
Stratling et al. (1984) Ca/Mg-dependent Endonuclease from Porcine Liver, May 10, 1984.
Tanuma et al. (1984) Multiple Forms of Nuclear Deoxyribonuclease in Rat Thymocytes. Biochem. Biophys. Res. Commun, Sep. 15, 1994.
Shiokawa et al. (1994) Identification of an endonuclease responsible for apoptosis in rat thymocytes. European Journal of Biochemistry 226:23-30, Nov. 1994.
Peitsch et al. (1993) Characterization of the endogenous deoxyribonuclease involved in nuclear DNA degradation during apoptosis (programmed cell death). The EMBO Journal 12 (1):371-377, Jan. 1993.

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