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High incidence of nitrosamine-induced tumorigenesis in mice lacking DNA repair methyltransferase
T Iwakuma1, K Sakumi, Y Nakatsuru
1Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Abstract:
The enzyme O6-methylguanine-DNA methyltransferase repairs alkylation-induced DNA damage, O6-methylguanine and O4-methylthymine, the former being formed more frequently. Previously, by means of gene targeting, we generated mice in which alleles for methyltransferase were disrupted. We now use these mouse lines, which are totally deficient in methyltransferase activity, to examine protective effects of the enzyme against tumor formation. In gene-targeted female mice given an i.p. injection of 5 mg/kg of dimethylnitrosamine, a larger number of liver and lung tumors occurred, as compared with normal female mice treated in the same manner. In male mice given a lower dose of carcinogen, the difference between normal and gene-targeted mice was statistically insignificant although more tumors did form in the gene-targeted mice. Methyltransferase apparently afforded protection from nitrosamine-induced tumorigenesis.
Insights
O6-methylguanine-DNA methyltransferase repairs DNA damage. Mice lacking this enzyme showed increased susceptibility to nitrosamine-induced tumors, indicating the enzyme
Area of Science:
- Biochemistry
- Genetics
- Toxicology
Background:
- O6-methylguanine-DNA methyltransferase (MGMT) is crucial for repairing DNA alkylation damage.
- MGMT repairs O6-methylguanine and O4-methylthymine, with O6-methylguanine being more common.
- Gene-targeting was previously used to create mice with disrupted methyltransferase alleles.
Purpose of the Study:
- To investigate the protective role of MGMT against chemically induced tumor formation.
- To assess tumor incidence in mice genetically deficient in MGMT activity.
Main Methods:
- Generation of mouse lines completely deficient in MGMT activity via gene targeting.
- Administration of dimethylnitrosamine (a carcinogen) to both gene-targeted and normal mice.
- Comparison of tumor formation (liver and lung) between the two groups of mice.
Main Results:
- Gene-targeted female mice exhibited a higher incidence of liver and lung tumors after dimethylnitrosamine exposure compared to normal mice.
- In male mice, while tumor incidence was higher in gene-targeted individuals, the difference was not statistically significant.
- These findings suggest a protective effect of MGMT against nitrosamine-induced tumorigenesis.
Conclusions:
- MGMT plays a significant role in protecting against DNA damage-induced cancer.
- The enzyme's deficiency increases susceptibility to carcinogens like dimethylnitrosamine.
- MGMT is a key factor in cancer prevention against specific types of DNA damage.