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Gene Review

Mgmt  -  O-6-methylguanine-DNA methyltransferase

Mus musculus

Synonyms: 6-O-methylguanine-DNA methyltransferase, AGT, AI267024, Agat, MGMT, ...
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Disease relevance of Mgmt


High impact information on Mgmt

  • The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA [5].
  • 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 [5].
  • We selected for G156A MGMT (triangle upMGMT) transduced LTRC present in 5 x 10(4) to 100 x 10(4) marrow cells infused into nonmyeloablated mice by the administration of O(6)-benzylguanine (BG) and BCNU every 3 to 4 weeks [6].
  • We have been testing the hypothesis that the pyridyloxobutylation pathway increases the mutagenic activity of the DNA methylation pathway by preventing the repair of O(6)-mG by O(6)-alkylguanine-DNA alkyltransferase (AGT) [7].
  • MGMT+/- mice were as resistant as MGMT+/+ mice, but some difference in survival time was noted when the two genotypes of mice were exposed to a relatively high dose of methylnitrosourea [3].

Chemical compound and disease context of Mgmt


Biological context of Mgmt

  • Although mutations stemming from O6-guanine alkylations would be predicted to be cumulative, we found no evidence of an Mgmt-dependent alteration in mutation spectrum in DNA samples from 12 month-old mice [12].
  • Mutational-reporter transgenes rescued from mice lacking either Mgmt, or both Mgmt and Msh6 suggest that O6-alkylguanine-induced miscoding does not contribute to the spontaneous mutational spectrum [12].
  • O6-methylguanine methyltransferase, Mgmt, constitutes the first line of defense against O6-alkylguanine, which can result in G : C to A : T transitions upon DNA replication [12].
  • Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice [1].
  • The 50% inhibitory concentration of O6-bG for inactivation of mouse AGT was >10-fold higher than for the human protein in MGMT-transfected Chinese hamster ovary (CHO) cells [2].

Anatomical context of Mgmt

  • As expected, Mgmt-deficient fibroblasts and bone marrow cells were not sensitive to UV light or to the crosslinking agent mitomycin C [13].
  • A dose of O6-bG, which inactivated human AGT, markedly sensitized human MGMT-transfected CHO cells to 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), whereas mouse MGMT-transfected CHO cells were much more resistant [2].
  • Recent reports dispute whether murine AGT, in cell-free systems, is less sensitive to O6-bG than the human AGT protein, raising the possibility that efficacy seen in the mouse host may not predict the therapeutic index observed in clinical trials [2].
  • However, despite successful depletion of MGMT activity in wild-type astrocytes by O(6)-benzylguanine (BG), resistance to BCNU persisted unchanged [14].
  • Repression of MLH1 and MGMT genes in colon mucosa adjacent to implanted cancer in athymic mouse [15].

Associations of Mgmt with chemical compounds


Regulatory relationships of Mgmt

  • The results give evidence for involvement of p53 in DNA damage-induced MGMT promoter activation [18].

Other interactions of Mgmt

  • Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant roles of these proteins in carcinogenesis [19].
  • To optimize our ability to detect mutations resulting from O6-alkylguanine-induced G : T mismatches, mice with combined deficiencies of Mgmt and the DNA mismatch repair molecule, Msh6, were analysed [12].
  • DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents [13].
  • A mutation of GGT to AGT at K-ras codon 12 was found by SSCP in one adenocarcinoma from a total of 19 specimens including 5 adenocarcinomas, 9 adenomatous hyperplastic regions, 1 squamous cell carcinoma and 4 normal-like stomach regions from 4 mice [20].
  • Thus, transfection mediated high level expression of p53 has inhibitory effect both on basal MGMT promoter activity and its activation by IR [18].

Analytical, diagnostic and therapeutic context of Mgmt


  1. A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice. Kawate, H., Itoh, R., Sakumi, K., Nakabeppu, Y., Tsuzuki, T., Ide, F., Ishikawa, T., Noda, T., Nawata, H., Sekiguchi, M. Carcinogenesis (2000) [Pubmed]
  2. Differential sensitivity of human and mouse alkyltransferase to O6-benzylguanine using a transgenic model. Liu, L., Lee, K., Wasan, E., Gerson, S.L. Cancer Res. (1996) [Pubmed]
  3. Methylnitrosourea-induced tumorigenesis in MGMT gene knockout mice. Sakumi, K., Shiraishi, A., Shimizu, S., Tsuzuki, T., Ishikawa, T., Sekiguchi, M. Cancer Res. (1997) [Pubmed]
  4. Mouse methyltransferase for repair of O6-methylguanine and O4-methylthymine in DNA. Kawate, H., Ihara, K., Kohda, K., Sakumi, K., Sekiguchi, M. Carcinogenesis (1995) [Pubmed]
  5. Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes. Kawate, H., Sakumi, K., Tsuzuki, T., Nakatsuru, Y., Ishikawa, T., Takahashi, S., Takano, H., Noda, T., Sekiguchi, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Limiting numbers of G156A O(6)-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Davis, B.M., Koç, O.N., Gerson, S.L. Blood (2000) [Pubmed]
  7. Interactions between methylating and pyridyloxobutylating agents in A/J mouse lungs: implications for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Peterson, L.A., Thomson, N.M., Crankshaw, D.L., Donaldson, E.E., Kenney, P.J. Cancer Res. (2001) [Pubmed]
  8. Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase. Allay, E., Reese, J.S., McGuire, E.A., Koç, O.N., Sedransk, N., Gerson, S.L. Oncogene (1997) [Pubmed]
  9. O6-alkylguanine-DNA alkyltransferase activity in epidermal tumor and normal epidermal cells of mice of various stocks and strains. Likhachev, A.J., Warren, B.S., Slaga, T.J. Carcinogenesis (1992) [Pubmed]
  10. Role of O6-alkylguanine-DNA alkyltransferase in protecting against 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced long-term toxicities. Hansen, R.J., Nagasubramanian, R., Delaney, S.M., Cherian, M.M., Lin, S., Kogan, S.C., Dolan, M.E. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  11. MGMT expression in murine bone marrow is a major determinant of animal survival after alkylating agent exposure. Reese, J.S., Qin, X., Ballas, C.B., Sekiguchi, M., Gerson, S.L. J. Hematother. Stem Cell Res. (2001) [Pubmed]
  12. Mutational-reporter transgenes rescued from mice lacking either Mgmt, or both Mgmt and Msh6 suggest that O6-alkylguanine-induced miscoding does not contribute to the spontaneous mutational spectrum. Sandercock, L.E., Kwok, M.C., Luchman, H.A., Mark, S.C., Giesbrecht, J.L., Samson, L.D., Jirik, F.R. Oncogene (2004) [Pubmed]
  13. DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents. Glassner, B.J., Weeda, G., Allan, J.M., Broekhof, J.L., Carls, N.H., Donker, I., Engelward, B.P., Hampson, R.J., Hersmus, R., Hickman, M.J., Roth, R.B., Warren, H.B., Wu, M.M., Hoeijmakers, J.H., Samson, L.D. Mutagenesis (1999) [Pubmed]
  14. O(6)-methylguanine-DNA methyltransferase activity, p53 gene status and BCNU resistance in mouse astrocytes. Nutt, C.L., Loktionova, N.A., Pegg, A.E., Chambers, A.F., Cairncross, J.G. Carcinogenesis (1999) [Pubmed]
  15. Repression of MLH1 and MGMT genes in colon mucosa adjacent to implanted cancer in athymic mouse. Kuniyasu, H., Sasaki, T., Sasahira, T., Chihara, Y., Ohmori, H. J. Exp. Clin. Cancer Res. (2004) [Pubmed]
  16. Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase. Shiraishi, A., Sakumi, K., Sekiguchi, M. Carcinogenesis (2000) [Pubmed]
  17. Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice. Hansen, R.J., Nagasubramanian, R., Delaney, S.M., Samson, L.D., Dolan, M.E. Carcinogenesis (2007) [Pubmed]
  18. p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents. Grombacher, T., Eichhorn, U., Kaina, B. Oncogene (1998) [Pubmed]
  19. Gene silencing in phenomena related to DNA repair. Mukai, T., Sekiguchi, M. Oncogene (2002) [Pubmed]
  20. Rare occurrence of ras and p53 gene mutations in mouse stomach tumors induced by N-methyl-N-nitrosourea. Furihata, C., Tatematsu, M., Saito, M., Ishida, S., Nakanishi, H., Inada, K., Tei, H., Hattori, M., Ito, T., Sakaki, Y. Jpn. J. Cancer Res. (1997) [Pubmed]
  21. Dual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase. Southgate, T.D., Garside, E., Margison, G.P., Fairbairn, L.J. The journal of gene medicine. (2006) [Pubmed]
  22. O6-methylguanine-DNA methyltransferase (MGMT) transfectants of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive colon cancer cell line selectively repopulate heterogenous MGMT+/MGMT- xenografts after BCNU and O6-benzylguanine plus BCNU. Phillips, W.P., Willson, J.K., Markowitz, S.D., Zborowska, E., Zaidi, N.H., Liu, L., Gordon, N.H., Gerson, S.L. Cancer Res. (1997) [Pubmed]
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