Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes.
Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/- MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/- MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.
Kawate
H
H
Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Sakumi
K
K
Tsuzuki
T
T
Nakatsuru
Y
Y
Ishikawa
T
T
Takahashi
S
S
Takano
H
H
Noda
T
T
Sekiguchi
M
M
D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D002352:Carrier Proteins; D004260:DNA Repair; D005260:Female; D008223:Lymphoma / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008770:Methylnitrosourea; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000502:physiology*; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents; D002352:Carrier Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D008770:Methylnitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1