遺伝子異常と発がん
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概要
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The frequency of errors during a single cycle of DNA replication is less than 10^<-10> per base pair. This high accuracy is ascribed to three independent steps of DNA replication ; base selection by DNA polymerase, elimination of mismatched nucleotide by proofreading exonuclease and post-replication mismatch repair. In addition, elimination of mutagenic substrate from the precursor pool and repair of damaged DNA template are involved. Defect in any one of genes controlling the above mentioned steps would cause high frequency of spontaneous mutation. Significance of genetic instablility in carcinogenesis is discussed, with special reference to hereditary cancer. 8-Oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate) is produced by active oxygen species in the nucleotide poll of the cell and can be incorporated into cellular DNA. Human cells contain enzyme activity that hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing occurrence of mutations, caused by misincorporation. When the cDNA for human 8-oxo-dGTPase was expressed in Escherichia coli mutT^- mutant cells devoid of self 8-oxo-dGTPase activity, the elevated level of spontaneous A : T to C : G mutation frequency reverted to normal. We isolated the genomic sequence encoding the enzyme and named the gene MTH1 (for mutT homologue). This gene is composed of at least 5 exons, spans approximately 9kb, and is located on human chromosome 7p22. To establish roles of the enzyme in carcinogenesis, mice defective in the gene is being constructed. Alkylation of DNA at the O^6 position of guanine is one of the most critical events leading to induction of mutation as well as cancer. The enzyme O^6-methylguanine-DNA methyltransferase repairs this and related lesions in DNA. By means of gene targeting, we established mouse lines deficient in the methyltransferase gene, and tissues from these mice contained no methyltransferase activity. Administration of methylnitrosourea to these gene-targeted mice led to early death, and normal mice treated in the same manner showed no untoward effects. In mice given methylnitrosourea treatment, the bone marrow became hypocellular and there was a drastic decrease in the number of leukocytes and platelets, thereby indicating an impaired reproductive capacity of hematopoietic stem cells.
- 福岡歯科大学学会の論文
- 1998-06-30
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