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Gene Review

MGMT  -  O-6-methylguanine-DNA methyltransferase

Homo sapiens

Synonyms: 6-O-methylguanine-DNA methyltransferase, Methylated-DNA--protein-cysteine methyltransferase, O-6-methylguanine-DNA-alkyltransferase

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Disease relevance of MGMT


Psychiatry related information on MGMT


High impact information on MGMT


Chemical compound and disease context of MGMT


Biological context of MGMT

  • Thus, through a change in conformation upon repair of the 6RG lesion, MGMT switches from a DNA repair factor to a transcription regulator (R-MGMT), enabling the cell to sense as well as respond to mutagens [21].
  • Second, R-MGMT, which adopts an altered conformation, utilizes its exposed VLWKLLKVV peptide domain (codons 98 to 106) to bind ER [21].
  • Methylation of the promoter region of the MGMT gene was determined using methylation-specific PCR and was present in 27 of 92 (29%) tumors [3].
  • The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum [2].
  • Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny [2].

Anatomical context of MGMT


Associations of MGMT with chemical compounds

  • O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from the O6 position of guanine [1].
  • Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0-9.2) [2].
  • These results indicate that MGMT is the primary mechanism for temozolomide resistance, but in the absence of MGMT, proficient mismatch repair determines sensitivity to this agent [25].
  • Cells transduced with Ha-MDR-IRES-MGMT showed higher resistance to vincristine and lower resistance to ACNU than those transduced with Ha-MGMT-IRES-MDR [24].
  • In the 16 patients treated with temozolamide plus cisplatin, no significant correlation between MGMT methylation status and response was observed, whereas in BCNU-treated patients, a significant difference was observed in favor of those with methylated MGMT [15].
  • Evidence from cysteine/methionine deprivation, acivicin treatment, and protein synthesis measurements in OTC-treated cells suggested that an increased cysteine flux also contributed significantly to enhanced MGMT expression [26].
  • Interestingly, combined treatment of GBM12 flank xenografts with temozolomide and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of temozolomide resistance by MGMT overexpression as compared with treatment with temozolomide alone [27].

Physical interactions of MGMT

  • Furthermore, MeCP2 preferentially bound to the CpG-methylated island in the MGMT negative line [28].
  • Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene [29].

Enzymatic interactions of MGMT

  • EXPERIMENTAL DESIGN: MGMT hypermethylation, expressed as the ratio between methylated MGMT to unmethylated MYOD1 in genomic DNA, was analyzed in normal and matching tumor tissue from 90 patients with NSCLC, and a control group of 10 patients without cancer using a methylation-specific fluorogenic Real-Time PCR (Taqman) system [30].
  • Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide [31].

Regulatory relationships of MGMT

  • No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed [32].
  • CONCLUSIONS: These data suggest that the Leu84Phe polymorphism affect the capacity of MGMT to inhibit estrogen receptor-mediated cell proliferation and is associated with breast cancer risk [33].
  • Because, a marginal enhancement of this protein may be adequate for genomic protection, we studied alterations in MGMT activity and expression in human peripheral blood lymphocytes and cancer cell lines induced by water-soluble and alcohol-soluble constituents of several plants with established antioxidant and medicinal properties [34].
  • Transgenic expression of hMGMT significantly but incompletely blocked MNU lymphomagenesis in PMS2-/- mice [35].
  • To test this, we examined apoptosis triggered by O(6)MeG in human peripheral lymphocytes in which O(6)-methylguanine-DNA methyltransferase (MGMT) had been inactivated by O(6)-benzylguanine (O(6)BG) and which were not proliferating or proliferating upon CD3/CD28 stimulation [36].

Other interactions of MGMT

  • From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively [37].
  • The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples] [38].
  • Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013) [39].
  • In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A [40].
  • None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs [40].

Analytical, diagnostic and therapeutic context of MGMT

  • A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry [41].
  • The expression levels of P-glycoprotein or MGMT in the transduced cells determined by FACS and Western blot analysis correlated well with the extent of resistance to vincristine and ACNU, respectively [24].
  • Exposure of buccal cell cultures to various organic or water-based extracts of products related to the use of tobacco and betel quid, decreased both cell survival (measured by reduction of tetrazolium dye) and MGMT activity (measured subsequently to the exposures in cellular extracts) [42].
  • In a previous study, we constructed two bicistronic retroviral vectors, Ha-MDR-IRES-MGMT and Ha-MGMT-IRES-MDR, that allow co-expression of the MGMT gene and the MDR1 gene to protect cells from the toxicity of combination chemotherapy [19].
  • Therefore, we isolated MGMT-interacting proteins from extracts of HT29 human colon cancer cells using affinity chromatography on MGMT-Sepharose [43].


  1. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Esteller, M., Toyota, M., Sanchez-Cespedes, M., Capella, G., Peinado, M.A., Watkins, D.N., Issa, J.P., Sidransky, D., Baylin, S.B., Herman, J.G. Cancer Res. (2000) [Pubmed]
  2. Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. Gilliland, F.D., Harms, H.J., Crowell, R.E., Li, Y.F., Willink, R., Belinsky, S.A. Cancer Res. (2002) [Pubmed]
  3. O(6)-Methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer. Wolf, P., Hu, Y.C., Doffek, K., Sidransky, D., Ahrendt, S.A. Cancer Res. (2001) [Pubmed]
  4. Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Hoon, D.S., Spugnardi, M., Kuo, C., Huang, S.K., Morton, D.L., Taback, B. Oncogene (2004) [Pubmed]
  5. MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Ogino, S., Hazra, A., Tranah, G.J., Kirkner, G.J., Kawasaki, T., Nosho, K., Ohnishi, M., Suemoto, Y., Meyerhardt, J.A., Hunter, D.J., Fuchs, C.S. Carcinogenesis (2007) [Pubmed]
  6. Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres. Sciuscio, D., Diserens, A.C., van Dommelen, K., Martinet, D., Jones, G., Janzer, R.C., Pollo, C., Hamou, M.F., Kaina, B., Stupp, R., Levivier, M., Hegi, M.E. Clin. Cancer Res. (2011) [Pubmed]
  7. Effect of alcohol drinking on gene expression of hepatic O6-methylguanine DNA methyltransferase in chronic liver diseases. Miyakawa, H., Liu, J., Noguchi, O., Marumo, F., Sato, C. Alcohol. Clin. Exp. Res. (1996) [Pubmed]
  8. Treatment of unresectable glioblastoma multiforme. Nieder, C., Grosu, A.L., Astner, S., Molls, M. Anticancer Res. (2005) [Pubmed]
  9. Cytochrome P-450 isozyme pattern is related to individual susceptibility to diethylnitrosamine-induced liver cancer in rats. Aitio, A., Aitio, M.L., Camus, A.M., Cardis, E., Bartsch, H. Jpn. J. Cancer Res. (1991) [Pubmed]
  10. O6-methylguanine-DNA methyltransferase in lymphocytes of the elderly with and without Alzheimer's disease. Edwards, J.A., Wang, L.G., Setlow, R.B., Kaminskas, E. Mutat. Res. (1989) [Pubmed]
  11. DNA repair in eukaryotes. Wood, R.D. Annu. Rev. Biochem. (1996) [Pubmed]
  12. The DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. Quinn, D.I. N. Engl. J. Med. (2001) [Pubmed]
  13. The DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. Buckner, J.C., Moynihan, T.J. N. Engl. J. Med. (2001) [Pubmed]
  14. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. Esteller, M., Garcia-Foncillas, J., Andion, E., Goodman, S.N., Hidalgo, O.F., Vanaclocha, V., Baylin, S.B., Herman, J.G. N. Engl. J. Med. (2000) [Pubmed]
  15. O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Balaña, C., Ramirez, J.L., Taron, M., Roussos, Y., Ariza, A., Ballester, R., Sarries, C., Mendez, P., Sanchez, J.J., Rosell, R. Clin. Cancer Res. (2003) [Pubmed]
  16. Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes. Grombacher, T., Mitra, S., Kaina, B. Carcinogenesis. (1996) [Pubmed]
  17. Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Boldogh, I., Ramana, C.V., Chen, Z., Biswas, T., Hazra, T.K., Grösch, S., Grombacher, T., Mitra, S., Kaina, B. Cancer. Res. (1998) [Pubmed]
  18. Expression of DNA repair proteins hMSH2, hMSH6, hMLH1, O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in melanoma cells with acquired drug resistance. Lage, H., Christmann, M., Kern, M.A., Dietel, M., Pick, M., Kaina, B., Schadendorf, D. Int. J. Cancer (1999) [Pubmed]
  19. Efficient protection of cells from the genotoxicity of nitrosoureas by the retrovirus-mediated transfer of human O6-methylguanine-DNA methyltransferase using bicistronic vectors with human multidrug resistance gene 1. Suzuki, M., Sugimoto, Y., Tsuruo, T. Mutat. Res. (1998) [Pubmed]
  20. Immunohistochemical analysis of DNA mismatch repair protein and O6-methylguanine-DNA methyltransferase in melanoma metastases in relation to clinical response to DTIC-based chemotherapy. Ma, S., Egyházi, S., Ringborg, U., Hansson, J. Oncol. Rep. (2002) [Pubmed]
  21. The modified human DNA repair enzyme O(6)-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage. Teo, A.K., Oh, H.K., Ali, R.B., Li, B.F. Mol. Cell. Biol. (2001) [Pubmed]
  22. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Belinsky, S.A., Palmisano, W.A., Gilliland, F.D., Crooks, L.A., Divine, K.K., Winters, S.A., Grimes, M.J., Harms, H.J., Tellez, C.S., Smith, T.M., Moots, P.P., Lechner, J.F., Stidley, C.A., Crowell, R.E. Cancer Res. (2002) [Pubmed]
  23. Evidence for nucleotide excision repair as a modifying factor of O6-methylguanine-DNA methyltransferase-mediated innate chloroethylnitrosourea resistance in human tumor cell lines. Chen, Z.P., Malapetsa, A., McQuillan, A., Marcantonio, D., Bello, V., Mohr, G., Remack, J., Brent, T.P., Panasci, L.C. Mol. Pharmacol. (1997) [Pubmed]
  24. Retroviral coexpression of two different types of drug resistance genes to protect normal cells from combination chemotherapy. Suzuki, M., Sugimoto, Y., Tsukahara, S., Okochi, E., Gottesman, M.M., Tsuruo, T. Clin. Cancer Res. (1997) [Pubmed]
  25. Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Middlemas, D.S., Stewart, C.F., Kirstein, M.N., Poquette, C., Friedman, H.S., Houghton, P.J., Brent, T.P. Clin. Cancer Res. (2000) [Pubmed]
  26. Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines. Niture, S.K., Velu, C.S., Smith, Q.R., Bhat, G.J., Srivenugopal, K.S. Carcinogenesis (2007) [Pubmed]
  27. Inhibition of Histone Deacetylation Potentiates the Evolution of Acquired Temozolomide Resistance Linked to MGMT Upregulation in Glioblastoma Xenografts. Kitange, G.J., Mladek, A.C., Carlson, B.L., Schroeder, M.A., Pokorny, J.L., Cen, L., Decker, P.A., Wu, W., Lomberk, G.A., Gupta, S.K., Urrutia, R.A., Sarkaria, J.N. Clin. Cancer Res. (2012) [Pubmed]
  28. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Nakagawachi, T., Soejima, H., Urano, T., Zhao, W., Higashimoto, K., Satoh, Y., Matsukura, S., Kudo, S., Kitajima, Y., Harada, H., Furukawa, K., Matsuzaki, H., Emi, M., Nakabeppu, Y., Miyazaki, K., Sekiguchi, M., Mukai, T. Oncogene (2003) [Pubmed]
  29. Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene. Pieper, R.O., Patel, S., Ting, S.A., Futscher, B.W., Costello, J.F. J. Biol. Chem. (1996) [Pubmed]
  30. Quantitative O(6)-methylguanine DNA methyltransferase methylation analysis in curatively resected non-small cell lung cancer: associations with clinical outcome. Brabender, J., Usadel, H., Metzger, R., Schneider, P.M., Park, J., Salonga, D., Tsao-Wei, D.D., Groshen, S., Lord, R.V., Takebe, N., Schneider, S., Hölscher, A.H., Danenberg, K.D., Danenberg, P.V. Clin. Cancer Res. (2003) [Pubmed]
  31. IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Natsume, A., Ishii, D., Wakabayashi, T., Tsuno, T., Hatano, H., Mizuno, M., Yoshida, J. Cancer Res. (2005) [Pubmed]
  32. Methylenetetrahydrofolate reductase genotype in diffuse large B-cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. Toffoli, G., Rossi, D., Gaidano, G., Cecchin, E., Boiocchi, M., Carbone, A. Int. J. Biol. Markers (2003) [Pubmed]
  33. Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk. Han, J., Tranah, G.J., Hankinson, S.E., Samson, L.D., Hunter, D.J. Pharmacogenet. Genomics (2006) [Pubmed]
  34. Chemopreventative strategies targeting the MGMT repair protein: augmented expression in human lymphocytes and tumor cells by ethanolic and aqueous extracts of several Indian medicinal plants. Niture, S.K., Rao, U.S., Srivenugopal, K.S. Int. J. Oncol. (2006) [Pubmed]
  35. Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT. Qin, X., Liu, L., Gerson, S.L. Oncogene (1999) [Pubmed]
  36. Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Roos, W., Baumgartner, M., Kaina, B. Oncogene (2004) [Pubmed]
  37. Aberrant DNA methylation as a cancer-inducing mechanism. Esteller, M. Annu. Rev. Pharmacol. Toxicol. (2005) [Pubmed]
  38. Epigenetic patterns in the progression of esophageal adenocarcinoma. Eads, C.A., Lord, R.V., Wickramasinghe, K., Long, T.I., Kurumboor, S.K., Bernstein, L., Peters, J.H., DeMeester, S.R., DeMeester, T.R., Skinner, K.A., Laird, P.W. Cancer Res. (2001) [Pubmed]
  39. CpG island methylation of DNA damage response genes in advanced ovarian cancer. Teodoridis, J.M., Hall, J., Marsh, S., Kannall, H.D., Smyth, C., Curto, J., Siddiqui, N., Gabra, H., McLeod, H.L., Strathdee, G., Brown, R. Cancer Res. (2005) [Pubmed]
  40. Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. Honorio, S., Agathanggelou, A., Wernert, N., Rothe, M., Maher, E.R., Latif, F. Oncogene (2003) [Pubmed]
  41. Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. Kang, G.H., Lee, S., Lee, H.J., Hwang, K.S. J. Pathol. (2004) [Pubmed]
  42. O6-methylguanine-DNA methyltransferase activity in human buccal mucosal tissue and cell cultures. Complex mixtures related to habitual use of tobacco and betel quid inhibit the activity in vitro. Liu, Y., Egyhazi, S., Hansson, J., Bhide, S.V., Kulkarni, P.S., Grafström, R.C. Carcinogenesis (1997) [Pubmed]
  43. Proteomic analysis of human O6-methylguanine-DNA methyltransferase by affinity chromatography and tandem mass spectrometry. Niture, S.K., Doneanu, C.E., Velu, C.S., Bailey, N.I., Srivenugopal, K.S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
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