Biopolym. Cell. 2013; 29(2):99-106.
MGMT expression: insights into its regulation. 1. Epigenetic factors
1Iatsyshyna A. P.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


O6-methylguanine-DNA methyltransferase (MGMT) is the DNA repair enzyme responsible for removing of alkylation adducts from the O6-guanine in DNA. Despite MGMT prevents mutations and cell death, this enzyme can provide resistance of cancer cells to alkylating agents of chemotherapy. The high intra- and inter-individual variations in the human MGMT expression level have been observed indicating to a complicated regulation of this gene. This review is focused on the study of epigenetic factors which could be potentially involved in regulation of the human MGMT gene expression. These include chromatin remodeling via histone modifications and DNA methylation of promoter region and gene body, as well as RNA-based mechanisms, alternative splicing, protein post- translational modifications, and other.
Keywords: O6-methylguanine-DNA methyltransferase (MGMT), epigenetic regulation of gene expression, methylation, chromatin remodeling


[1] Pegg A. E., Dolan M. E., Moschel R. C. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase Prog. Nucleic Acid Res. Mol. Biol 1995 51 P. 167–223.
[2] Kaina B., Christmann M., Naumann S., Roos W. P. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents DNA Repair (Amst) 2007 6, N 8 P. 1079–1099.
[3] Verbeek B., Southgate T. D., Gilham D. E., Margison G. P. O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy Br. Med. Bull 2008 85 P. 17–33.
[4] Hegi M. E., Liu L., Herman J. G., Stupp R., Wick W., Weller M., Mehta M. P., Gilbert M. R. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity J. Clin. Oncol 2008 26, N 25 P. 4189–4199.
[5] Margison G. P., Povey A. C., Kaina B., Santibanez-Koref M. F. Variability and regulation of O6-alkylguanine-DNA alkyltransferase Carcinogenesis 2003 24, N 4 P. 625–635.
[6] Sagher D., Karrison T., Schwartz J. L., Larson R. A., Strauss B. Heterogeneity of O6-alkylguanine-DNA alkyltransferase activity in peripheral blood lymphocytes: relationship between this activity in lymphocytes and in lymphoblastoid lines from normal controls and from patients with Hodgkin's disease or non-Hodgkin's lymphoma Cancer Res 1989 49, N 19 P. 5339–5344.
[7] Arita I., Fujimori A., Takebe H., Tatsumi K. Evidence for spontaneous conversion of Mex– to Mex+ in human lymphoblastoid cells Carcinogenesis 1990 11, N 10 P. 1733–1738.
[8] Strauss B. S. The control of O6-methylguanine-DNA methyltransferase (MGMT) activity in mammalian cells: a pre-molecular view Mutat. Res 1990 233, N 1–2 P. 139–150.
[9] Iatsyshyna A. P., Lylo V. V., Pidpala O. V., Ruban T. P., Vagina I. M., Lukash L.L. The expression of O6-methylguanine-DNA methyltransferase in the spontaneously immortalized mouse cell line G1 and its sublines G1-OA and G1-T Biopolym. Cell 2007 23, N 3 P. 250–254.
[10] Meyer L. R., Zweig A. S., Hinrichs A. S., Karolchik D., Kuhn R. M., Wong M., Sloan C. A., Rosenbloom K. R., Roe G., Rhead B., Raney B. J., Pohl A., Malladi V. S., Li C. H., Lee B. T., Learned K., Kirkup V., Hsu F., Heitner S., Harte R. A., Haeussler M., Guruvadoo L., Goldman M., Giardine B. M., Fujita P. A., Dreszer T. R., Diekhans M., Cline M. S., Clawson H., Barber G. P., Haussler D., Kent W. J. The UCSC Genome Browser database: extensions and updates 2013 Nucleic Acids Res 2013 41, Database issue D64–69.
[11] Kent W. J., Sugnet C. W., Furey T. S., Roskin K. M., Pringle T. H., Zahler A. M., Haussler D. The human genome browser at UCSC Genome Res 2002 12, N 6 P. 996–1006.
[12] Pegg A. E. Methylation of the O6 position of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents Cancer Invest 1984 2, N 3 P. 223–231.
[13] Singer B. Alkylation of the O6 of guanine is only one of many chemical events that may initiate carcinogenesis Cancer Invest 1984 2, N 3 P. 233–238.
[14] Iatsyshyna A. Current approaches to improve the anticancer chemotherapy with alkylating agents: state of the problem in world and Ukraine Biopolym. Cell 2012 28, N 2 P. 83–92.
[15] Tubbs J. L., Pegg A. E., Tainer J. A. DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy DNA Repair (Amst) 2007 6, N 8 P. 1100–1115.
[16] Pegg A. E., Dolan M. E., Scicchitano D., Morimoto K. Studies of the repair of O6-alkylguanine and O4-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria Environ. Health Perspect 1985 62 P. 109–114.
[17] Janssen K., Eichhorn-Grombacher U., Schlink K., Nitzsche S., Oesch F., Kaina B. Long-time expression of DNA repair enzymes MGMT and APE in human peripheral blood mononuclear cells Arch. Toxicol 2001 75, N 5 P. 306–312.
[18] Gerson S. L., Trey J. E., Miller K., Berger N. A. Comparison of O6-alkylguanine-DNA alkyltransferase activity based on cellular DNA content in human, rat and mouse tissues Carcinogenesis 1986 7, N 5 P. 745–749.
[19] Lenhard B., Sandelin A., Carninci P. Metazoan promoters: emerging characteristics and insights into transcriptional regulation Nat. Rev. Genet 2012 13, N 4 P. 233–245.
[20] Deaton A. M., Bird A. CpG islands and the regulation of transcription Genes Dev 2011 25, N 10 P. 1010–1022.
[21] Harris L. C., Potter P. M., Tano K., Shiota S., Mitra S., Brent T. P. Characterization of the promoter region of the human O6-methylguanine-DNA methyltransferase gene Nucleic Acids Res 1991 19, N 22 P. 6163–6167.
[22] Maurano M. T., Humbert R., Rynes E., Thurman R. E., Haugen E., Wang H., Reynolds A. P., Sandstrom R., Qu H., Brody J., Shafer A., Neri F., Lee K., Kutyavin T., Stehling-Sun S., Johnson A. K., Canfield T. K., Giste E., Diegel M., Bates D., Hansen R. S., Neph S., Sabo P. J., Heimfeld S., Raubitschek A., Ziegler S., Cotsapas C., Sotoodehnia N., Glass I., Sunyaev S. R., Kaul R., Stamatoyannopoulos J. A. Systematic localization of common disease-associated variation in regulatory DNA Science 2012 337, N 6099 P. 1190–1195.
[23] Qian X., von Wronski M. A., Brent T. P. Localization of methylation sites in the human O6-methylguanine-DNA methyltransferase promoter: correlation with gene suppression Carcinogenesis 1995 16, N 6 P. 1385–1390.
[24] Esteller M., Hamilton S. R., Burger P. C., Baylin S. B., Herman J. G. Inactivation of the DNA repair gene O6-methylguanineDNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia Cancer Res 1999 59, N 4 P. 793–797.
[25] Herath N. I., Walsh M. D., Kew M., Smith J. L., Jass J. R., Young J., Leggett B. A., Macdonald G. A. Silencing of O6-methylguanine DNA methyltransferase in the absence of promoter hypermethylation in hepatocellular carcinomas from Australia and South Africa Oncol. Rep 2007 17, N 4 P. 817–822.
[26] Danam R. P., Howell S. R., Remack J. S., Brent T. P. Heterogeneous methylation of the O(6)-methylguanine-DNA methyltransferase promoter in immortalized IMR90 cell lines Int. J. Oncol 2001 18, N 6 P. 1187–1193.
[27] Esteller M., Garcia-Foncillas J., Andion E., Goodman S. N., Hidalgo O. F., Vanaclocha V., Baylin S. B., Herman J. G. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents N. Engl. J. Med 2000 343, N 19 P. 1350–1354.
[28] Esteller M., Gaidano G., Goodman S. N., Zagonel V., Capello D., Botto B., Rossi D., Gloghini A., Vitolo U., Carbone A., Baylin S. B., Herman J. G. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma J. Natl Cancer Inst 2002 94, N 1 P. 26–32.
[29] Soejima H., Zhao W., Mukai T. Epigenetic silencing of the MGMT gene in cancer Biochem. Cell Biol 2005 83, N 4 P. 429–437.
[30] Maier S., Dahlstroem C., Haefliger C., Plum A., Piepenbrock C. Identifying DNA methylation biomarkers of cancer drug response Am. J. Pharmacogenomics 2005 5, N 4 P. 223–232.
[31] Esteller M., Herman J. G. Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer Oncogene 2004 23, N 1 P. 1–8.
[32] Park T. J., Han S. U., Cho Y. K., Paik W. K., Kim Y. B., Lim I. K. Methylation of O(6)-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma Cancer 2001 92, N 11 P. 2760–2768.
[33] Wang Y., Kato T., Ayaki H., Ishizaki K., Tano K., Mitra S., Ikenaga M. Correlation between DNA methylation and expression of O6-methylguanine-DNA methyltransferase gene in cultured human tumor cells Mutat. Res 1992 273, N 2 P. 221–230.
[34] Harris L. C., Remack J. S., Houghton P. J., Brent T. P. Wild-type p53 suppresses transcription of the human O6-methylguanineDNA methyltransferase gene Cancer Res 1996 56, N 9 P. 2029–2032.
[35] Pieper R. O., Costello J. F., Kroes R. A., Futscher B. W., Marathi U., Erickson L. C. Direct correlation between methylation status and expression of the human O-6-methylguanine DNA methyltransferase gene Cancer Commun 1991 3, N 8 P. 241–253.
[36] Christmann M., Pick M., Lage H., Schadendorf D., Kaina B. Acquired resistance of melanoma cells to the antineoplastic agent fotemustine is caused by reactivation of the DNA repair gene MGMT Int. J. Cancer 2001 92, N 1 P. 123–129.
[37] Jones P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond Nat. Rev. Genet 2012 13, N 7 P. 484–492.
[38] Bhakat K. K., Mitra S. CpG methylation-dependent repression of the human O6-methylguanine-DNA methyltransferase gene linked to chromatin structure alteration Carcinogenesis 2003 24, N 8 P. 1337–1345.
[39] Danam R. P., Howell S. R., Brent T. P., Harris L. C. Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins Mol. Cancer Ther 2005 4, N 1 P. 61–69.
[40] Pieper R. O., Patel S., Ting S. A., Futscher B. W., Costello J. F. Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene J. Biol. Chem 1996 271, N 23 P. 13916–13924.
[41] Costello J. F., Futscher B. W., Kroes R. A., Pieper R. O. Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6methylguanine DNA methyltransferase gene in human glioma cell lines Mol. Cell Biol 1994 14, N 10 P. 6515–6521.
[42] Patel S. A., Graunke D. M., Pieper R. O. Aberrant silencing of the CpG island-containing human O6-methylguanine DNA methyltransferase gene is associated with the loss of nucleosome-like positioning Mol. Cell Biol 1997 17, N 10 P. 5813–5822.
[43] 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. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer Oncogene 2003 22, N 55 P. 8835–8844.
[44] Zhao W., Soejima H., Higashimoto K., Nakagawachi T., Urano T., Kudo S., Matsukura S., Matsuo S., Joh K., Mukai T. The essential role of histone H3 Lys9 di-methylation and MeCP2 binding in MGMT silencing with poor DNA methylation of the promoter CpG island J. Biochem 2005 137, N 3 P. 431–440.
[45] Pieper R. O., Lester K. A., Fanton C. P. Confluence-induced alterations in CpG island methylation in cultured normal human fibroblasts Nucleic Acids Res 1999 27, N 15 P. 3229–3235.
[46] Yamada H., Vijayachandra K., Penner C., Glick A. Increased sensitivity of transforming growth factor (TGF) beta 1 null cells to alkylating agents reveals a novel link between TGFbeta signaling and O(6)-methylguanine methyltransferase promoter hypermethylation J. Biol. Chem 2001 276, N 22 P. 19052–19058.
[47] Friedman R. C., Farh K. K., Burge C. B., Bartel D. P. Most mammalian mRNAs are conserved targets of microRNAs Genome Res 2009 19, N 1 P. 92–105.
[48] Li Z., Rana T. M. Molecular mechanisms of RNA-triggered gene silencing machineries Acc. Chem. Res 2012 45, N 7 P. 1122–1131.
[49] Singh R. K., Cooper T. A. Pre-mRNA splicing in disease and therapeutics Trends Mol. Med 2012 18, N 8 P. 472–482.
[50] Iatsyshyna A. P., Nidoieva Z. M., Pidpala O. V., Lukash L. L. Bioinformatic analysis of potential post-translational modification sites of the human O6-methylg uanine-DNA methylt ransferase (MGMT) protein Ukr. Biokhim. Zh 2012 84, N 6 P. 74–85.
[51] Lee C., Atanelov L., Modrek B., Xing Y. ASAP: the Alternative Splicing Annotation Project Nucleic Acids Res 2003 31, N 1 P. 101–105.
[52] Sanchez-Pla A., Reverter F., Ruiz de Villa M. C., Comabella M. Transcriptomics: mRNA and alternative splicing J. Neuroimmunol 2012 248, N 1–2 P. 23–31.