Repair of O6-alkylguanine by alkyltransferases

Pegg, Anthony E

doi:10.1016/s1383-5742(00)00017-x

Cited by 576DNA Repair MechanismsCarcinogens and Genotoxicity AssessmentEpigenetics and DNA Methylation

Repair of O6-alkylguanine by alkyltransferases

Pegg, Anthony E·2000·Mutation Research/Reviews in Mutation Research

DOI 10.1016/s1383-5742(00)00017-x

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Abstract

The predominant pathway for the repair of O(6)-methylguanine in DNA is via the activity of an alkyltransferase protein that transfers the methyl group to a cysteine acceptor site on the protein itself. This review article describes recent studies on this alkyltransferase. The protein repairs not only methyl groups but also 2-chloroethyl-, benzyl- and pyridyloxobutyl-adducts. It acts on double-stranded DNA by flipping the O(6)-guanine adduct out of the DNA helix and into a binding pocket. The free base, O(6)-benzylguanine, is able to bind in this pocket and react with the cysteine, rendering it an effective inactivator of mammalian alkyltransferases. The alkylated form of the protein is rapidly degraded by the ubiquitin/proteasomal system. Some tumor cells do not express alkyltransferase despite having an intact gene. Methylation of key sites in CpG-rich islands in the promoter region are involved in this silencing and a change in the nuclear localization of an enhancer binding protein may also contribute. The alkyltransferase promoter contains Sp1, GRE and AP-1 sites and is slightly inducible by glucocorticoids and protein kinase C activators. There is a complex relationship between p53 and alkyltransferase expression with p53 mediating a rise in alkyltransferase in response to ionizing radiation but having no clear effect on basal levels. DNA adducts at the O(6)-position of guanine are a major factor in the carcinogenic, mutagenic, apoptopic and clastogenic actions of methylating agents and chloroethylating agents. Studies with transgenic mice in which alkyltransferase levels are increased or decreased confirm the importance of this repair pathway in protecting against carcinogenesis. Alkyltransferase activity in tumors protects them from therapeutic agents such as temozolomide and BCNU. This resistance is abolished by O(6)-benzylguanine and this drug is currently in clinical trials to enhance cancer chemotherapy by these agents. Studies are in progress to reduce the toxicity of such therapy towards the bone marrow by gene therapy to express alkyltransferases with mutations imparting resistance to O(6)-benzylguanine at high levels in marrow stem cells. Several polymorphisms in the human alkyltransferase gene have been identified but the significance of these in terms of alkyltransferase action is currently unknown.

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Schold, S. C., Kokkinakis, D. M., Rudy, J. L., Moschel, R. C., & Pegg, A. E. (1996) · PubMed · Cited by 38 · see citing works
Self-citation
Reaction and Binding of Oligodeoxynucleotides Containing Analogues of O6-Methylguanine with Wild-Type and Mutant Human O6-Alkylguanine-DNA Alkyltransferase
Spratt, T. E., Wu, J. D., Levy, D. E., Kanugula, S., & Pegg, A. E. (1999) · Biochemistry · doi:10.1021/bi982908w · Cited by 38 · see citing works
Self-citation
Relationship between O6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients.
Chen, Z. P., Yarosh, D. B., Garcia, Y., Tampieri, D. I., Mohr, G., Malapetsa, A., Langleben, A., & Panasci, L. (1999) · PubMed · Cited by 38 · see citing works
Point mutations in human O6-alkylguanine-DNA alkyltransferase prevent the sensitization by O6-benzylguanine to killing by N,N'-bis (2-chloroethyl)-N-nitrosourea.
Loktionova, N. A., & Pegg, A. E. (1996) · PubMed · Cited by 37 · see citing works
Self-citation
The nuclear targeting and nuclear retention properties of a human DNA repair protein O6‐methylguanine‐DNA methyltransferase are both required for its nuclear localization: the possible implications.
Lim, A., & Li, B. F. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00778.x · Cited by 36 · see citing works
Binding and repair of O6-ethylguanine in double-stranded oligodeoxynucleotides by recombinant human O6-alkylguanine-DNA alkyltransferase do not exhibit significant dependence on sequence context
Bender, K. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.11.2087 · Cited by 35 · see citing works
Conformational Change in Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase upon Alkylation of Its Active Site by SN1 (Indirect-Acting) and SN2 (Direct-Acting) Alkylating Agents: Breaking a “Salt-Link”?
Oh, H.-K., Teo, A. K.-C., Ali, R. B., Lim, A., Ayi, T.-C., Yarosh, D. B., & Li, B. F. L. (1996) · Biochemistry · doi:10.1021/bi9603635 · Cited by 35 · see citing works
Investigation of the Role of Tyrosine-114 in the Activity of Human O6-Alkylguanine-DNA Alkyltranferase
Goodtzova, K., Kanugula, S., Edara, S., & Pegg, A. E. (1998) · Biochemistry · doi:10.1021/bi9811718 · Cited by 35 · see citing works
Self-citation
Implication of Localization of Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase at Active Transcription Sites in Transcription-Repair Coupling of the Mutagenic O6-Methylguanine Lesion
Ali, R. B., Teo, A. K.-C., Oh, H.-K., Chuang, L. S.-H., Ayi, T.-C., & Li, B. F. L. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1660 · Cited by 35 · see citing works
Probing of conformational changes in human O6-alkylguanine-DNA alkyl transferase protein in its alkylated and DNA-bound states by limited proteolysis
Kanugula, S., Goodtzova, K., & PEGG, E. A. (1998) · Biochemical Journal · doi:10.1042/bj3290545 · Cited by 35 · see citing works
Immunohistochemical detection of the DNA repair enzyme O6-methylguanine-DNA methyltransferase in formalin-fixed, paraffin-embedded astrocytomas.
McLendon, R. E., Cleveland, L., Pegram, C. N., Bigner, S. H., Bigner, D. D., & Friedman, H. S. (1998) · PubMed · Cited by 34 · see citing works
Reversal of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced severe immunodeficiency by transduction of murine long-lived hemopoietic progenitor cells using O6-methylguanine DNA methyltransferase complementary DNA
Maze, R., Kapur, R., Kelley, M. R., Hansen, W. K., Oh, S.-J., & Williams, D. A. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.2.1006 · Cited by 33 · see citing works
Engineering human DNA alkyltransferases for gene therapy using random sequence mutagenesis.
Encell, L. P., Coates, M. M., & Loeb, L. A. (1998) · PubMed · Cited by 33 · see citing works
Fewer chromosome aberrations and earlier apoptosis induced by DNA synthesis inhibitors, a topoisomerase II inhibitor or alkylating agents in human cells with normal compared with mutant p53
Greenwood, S. K., Armstrong, M. J., Hill, R., Bradt, C. I., Johnson, T. E., Hilliard, C. A., & Galloway, S. M. (1998) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(97)00272-8 · Cited by 33 · see citing works
Expression of the inactive C145A mutant human O6-alkylguanine-DNA alkyltransferase in E.coli increases cell killing and mutations by N-methyl-N′-nitro-N-nitrosoguanidine
Edara, S., Kanugula, S., & Pegg, A. E. (1999) · Carcinogenesis · doi:10.1093/carcin/20.1.103 · Cited by 33 · see citing works
Self-citation
Creation of human alkyltransferases resistant to O6-benzylguanine.
Christians, F. C., Dawson, B. J., Coates, M. M., & Loeb, L. A. (1997) · PubMed · Cited by 33 · see citing works
Comparison of mutagenesis by O6-methyl- and O6-ethylguanine and O4- methylthymine in Escherichia coli using double-stranded and gapped plasmids
Pauly, G. T. (1998) · Carcinogenesis · doi:10.1093/carcin/19.3.457 · Cited by 33 · see citing works
Polymorphism in the human O6-methylguanine-DNA methyltransferase gene detected by PCR-SSCP analysis
Otsuka, M., Abe, M., Nakabeppu, Y., Sekiguchi, M., & Suzuki, T. (1996) · Pharmacogenetics · doi:10.1097/00008571-199608000-00010 · Cited by 32 · see citing works
Protection of CHO cells by mutant forms of O6-alkylguanine-DNA alkyltransferase from killing by 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine or O6-benzyl-8-oxoguanine
Loktionova, N. A., Xu‐Welliver, M., Crone, T. M., Kanugula, S., & Pegg, A. E. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00095-7 · Cited by 31 · see citing works
Self-citation
Specificities of human, rat andE.coliO6-methylguanine-DNA methyltransferases towards the repair of O6-methyl and O6-ethylguanine in DNA
Liem, L.-K., Lim, A., & Li, B. F. L. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.9.1613 · Cited by 31 · see citing works
Biallelic mutations of the Tsc2 gene in chemically induced rat renal cell carcinoma
Satake, N., Urakami, S., Hirayama, Y., Izumi, K., & Hino, O. (1998) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19980911)77:6 · Cited by 30 · see citing works
Mouse methyltransferase for repair of O6-methylguanine and O4-methylthymine in DNA
Kawate, H., Ihara, K., Kohda, K., Sakumi, K., & Sekiguchi, M. (1995) · Carcinogenesis · doi:10.1093/carcin/16.7.1595 · Cited by 30 · see citing works
Synthesis of DNA Oligonucleotides Containing Site-Specifically Incorporated O 6 -[4-Oxo-4-(3-pyridyl)butyl]guanine and Their Reaction with O 6 -Alkylguanine-DNA Alkyltransferase
Wang, L., Spratt, T. E., Pegg, A. E., & Peterson, L. A. (1999) · Chemical Research in Toxicology · doi:10.1021/tx980251+ · Cited by 29 · see citing works
Self-citation
BCNU is a caspase-mediated inhibitor of drug-induced apoptosis.
Peták, I., Mihalik, R., Bauer, P. I., Süli‐Vargha, H., Sebestyén, A. R., & Kopper, L. (1998) · PubMed · Cited by 28 · see citing works
Nickel(II) inhibits the repair of O 6 -methylguanine in mammalian cells
Iwitzki, F., Schlepegrell, R., Eichhorn, U., Kaina, B., Beyersmann, D., & Hartwig, A. (1998) · Archives of Toxicology · doi:10.1007/s002040050561 · Cited by 28 · see citing works
Identification and characterisation of the Drosophila melanogaster O6-alkylguanine-DNA alkyltransferase cDNA
Kooistra, R. A., Zonneveld, J. B. M., Lohman, P. H. M., Pastink, A., Watson, A. J., & Margison, G. P. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.8.1795 · Cited by 27 · see citing works
A new model for how O6-methylguanine-DNA methyltransferase binds DNA.
Vora, R. A., Pegg, A. E., & Ealick, S. E. (1998) · PubMed · Cited by 26 · see citing works
Self-citation
Inhibition of Human O6-Alkylguanine-DNA Alkyltransferase and Potentiation of the Cytotoxicity of Chloroethylnitrosourea by 4(6)-(Benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine Derivatives and Analogues
Terashima, I., & Kohda, K. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm970363i · Cited by 26 · see citing works
Point mutations at multiple sites including highly conserved amino acids maintain activity, but render O6-alkylguanine‒DNA alkyltransferase insensitive to O6-benzylguanine
Xu‐Welliver, M., & Pegg, A. E. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3470519 · Cited by 26 · see citing works
Self-citation
Role of Wild-Type p53 on the Antineoplastic Activity of Temozolomide Alone or Combined with Inhibitors of Poly(ADP-Ribose) Polymerase
Tentori, L., Lacal, P. M., Benincasa, E., Franco, D., Faraoni, I., Bonmassar, E., & Graziani, G. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37448-8 · Cited by 26 · see citing works
Role of codon 160 in the sensitivity of human O6-alkylguanine-DNA alkyltransferase to O6-benzylguanine
Xu‐Welliver, M., Leitão, J. M., Kanugula, S., Meehan, W. J., & Pegg, A. E. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00216-6 · Cited by 25 · see citing works
Self-citation
Alteration of the conserved residue tyrosine-158 to histidine renders human O6-alkylguanine-DNA alkyltransferase insensitive to the inhibitor O6-benzylguanine.
Xu‐Welliver, M., Leitão, J., Kanugula, S., & Pegg, A. E. (1999) · PubMed · Cited by 24 · see citing works
Self-citation
Intraarterial O 6 -benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea
Kurpad, S. N., Dolan, M. E., McLendon, R. E., Archer, G. E., Moschel, R. C., Pegg, A. E., Bigner, D. D., & Friedman, H. S. (1997) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800050577 · Cited by 24 · see citing works
Self-citation
Reaction ofO 6-Benzylguanine-resistant Mutants of Human O 6-Alkylguanine-DNA Alkyltransferase with O 6-Benzylguanine in Oligodeoxyribonucleotides
Pegg, A. E., Kanugula, S., Edara, S., Pauly, G. T., Moschel, R. C., & Goodtzova, K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.18.10863 · Cited by 24 · see citing works
Self-citation
Retroviral-Mediated Expression of the P140A, but not P140A/G156A, Mutant Form of O6-Methylguanine DNA Methyltransferase Protects Hematopoietic Cells against O6-Benzylguanine Sensitization to Chloroethylnitrosourea Treatment
Maze, R., Kurpad, C., Pegg, A. E., Erickson, L. C., & Williams, D. A. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35054-2 · Cited by 24 · see citing works
Self-citation
Lack of evidence for a polymorphism at codon 160 of human O6-alkylguanine-DNA alkyltransferase gene in normal tissue and cancer.
Mh, W., Ke, L., Oi, O., Kokkinakis, D. M., Hs, F., & Me, D. (1999) · PubMed · Cited by 23 · see citing works
Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase
Allay, E. R., Reese, J., McGuire, E. A., Koç, O. N., Sedransk, N., & Gerson, S. L. (1997) · Oncogene · doi:10.1038/sj.onc.1201384 · Cited by 23 · see citing works
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. V., Markowitz, S. D., Zborowska, E., Zaidi, N. H., Liu, L.-Z., Gordon, N. H., & Gerson, S. L. (1997) · PubMed · Cited by 22 · see citing works
Application of Antisense Ribonucleic Acid Complementary to O6-Methylguanine-deoxyribonucleic Acid Methyltransferase Messenger Ribonucleic Acid for Therapy of Malignant Gliomas
Nagane, M., Asai, A., Shibui, S., Nomura, K., & Kuchino, Y. (1997) · Neurosurgery · doi:10.1097/00006123-199708000-00021 · Cited by 22 · see citing works
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. (1998) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(98)00002-5 · Cited by 22 · see citing works
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. (1997) · Carcinogenesis · doi:10.1093/carcin/18.10.1889 · Cited by 21 · see citing works
Enhanced ultrasensitive detection of structurally diverse antigens using a single immuno-PCR assay protocol
Case, M. C., Burt, A. D., Hughes, J., Palmer, J. M., Collier, J. D., Bassendine, M. F., Yeaman, S. J., Hughes, M. A., & Major, G. N. (1999) · Journal of Immunological Methods · doi:10.1016/s0022-1759(98)00207-5 · Cited by 20 · see citing works
O 6 -Benzylguanine-mediated enhancement of nitrosourea activity in Mer − central nervous system tumor xenografts - implications for clinical trials
Keir, S. T., Dolan, M. E., Pegg, A. E., Lawless, A., Moschel, R. C., Bigner, D. D., & Friedman, H. S. (2000) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800051016 · Cited by 19 · see citing works
Self-citation
Specificity of DNA Repair Methyltransferases Determined by Competitive Inactivation with Oligonucleotide Substrates: Evidence That Escherichia coli Ada Repairs O6-Methylguanine and O4-Methylthymine with Similar Efficiency
Paalman, S. R., Sung, C., & Clarke, N. D. (1997) · Biochemistry · doi:10.1021/bi970740t · Cited by 19 · see citing works
Inefficient Repair of RNA · DNA Hybrids
Kamath‐Loeb, A. S., Hizi, A., Tabone, J. C., Solomon, M. S., & Loeb, L. A. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.0492a.x · Cited by 19 · see citing works
Differential sensitivity of human and mouse alkyltransferase to O6-benzylguanine using a transgenic model.
Liu, L., Lee, K. H., Wasan, E. K., & Gerson, S. L. (1996) · PubMed · Cited by 18 · see citing works
Methyl bromide causes DNA methylation in rats and mice but fails to induce somatic mutations in λlacZ transgenic mice
Pletsa, V. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00262-6 · Cited by 18 · see citing works
Repair of DNA lesion O 6 -methylguanine in hepatocellular carcinogenesis
Major, G. N., & Collier, J. D. (1998) · Journal of Hepato-Biliary-Pancreatic Surgery · doi:10.1007/s005340050059 · Cited by 17 · see citing works
Roles of DNA repair methyltransferase in mutagenesis and carcinogenesis
Sekiguchi, M., & Sakumi, K. (1997) · The Japanese Journal of Human Genetics · doi:10.1007/bf02766939 · Cited by 17 · see citing works
Transient Transfection of a Synthetic Hammerhead Ribozyme Targeted Against Human MGMT Gene to Cells in Culture Potentiates the Genotoxicity of the Alkylation Damage Induced by Mitozolomide
Citti, L., Eckstein, F., Capecchi, B., Mariani, L., Nevischi, S., Poggi, A. D., & Rainaldi, G. (1999) · Antisense and Nucleic Acid Drug Development · doi:10.1089/oli.1.1999.9.125 · Cited by 17 · see citing works
Conserved residue lysine165 is essential for the ability of O6-alkylguanine‒DNA alkyltransferase to react with O6-benzylguanine
Xu‐Welliver, M., Kanugula, S., Loktionova, N. A., Crone, T. M., & Pegg, A. E. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3470527 · Cited by 17 · see citing works
Self-citation
Effect of DNA on the Inactivation of O6-alkylguanine-DNA alkyltransferase by 9-Substituted O6-benzylguanine derivatives
Pegg, A. E., Chung, L., & Moschel, R. C. (1997) · Biochemical Pharmacology · doi:10.1016/s0006-2952(97)00060-9 · Cited by 17 · see citing works
Self-citation
O6-(Alkyl/aralkyl)guanosine and 2‘-Deoxyguanosine Derivatives: Synthesis and Ability To Enhance Chloroethylnitrosourea Antitumor Action
Mounetou, E., Débiton, E., Buchdahl, C., Gardette, D., Gramain, J., Maurizis, J., Veyre, A., & Madelmont, J. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm960881d · Cited by 16 · see citing works
Evidence for ubiquitin-mediated degradation of the DNA repair enzyme for O6-methylguanine in non-tumour derived human cell and tissue extracts
Major, G. N., BRADY, M., Notarianni, G., Collier, J. D., & Douglas, M. S. (1997) · Biochemical Society Transactions · doi:10.1042/bst025359s · Cited by 16 · see citing works
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. (1999) · Carcinogenesis · doi:10.1093/carcin/20.12.2361 · Cited by 15 · see citing works
Self-citation
Expression of the O6-alkylguanine-DNA alkyltransferase gene is elevated in human breast tumor cells.
Wani, G., & Sm, D. (1998) · PubMed · Cited by 15 · see citing works
Potentiation of BCNU antitumor efficacy by 9-substituted O 6-benzylguanines. Effect of metabolism
Kokkinakis, D. M., Moschel, R. C., Pegg, A. E., & Schold, S. C. (2000) · Cancer Chemotherapy and Pharmacology · doi:10.1007/pl00006746 · Cited by 14 · see citing works
Self-citation
Activity of O 6 -methylguanine DNA methyltransferase in mononuclear blood cells of formaldehyde-exposed medical students
Schlink, K., Janssen, K., Nitzsche, S., Gebhard, S., Hengstler, J. G., Klein, S., & Oesch, F. (1999) · Archives of Toxicology · doi:10.1007/s002040050581 · Cited by 14 · see citing works
Amplification of the DNA Repair GeneO 6-Methylguanine-DNA Methyltransferase Associated with Resistance to Alkylating Drugs in a Mammalian Cell Line
Tano, K., Dunn, W. C., Darroudi, F., Shiota, S., Preston, R. J., Natarajan, A. T., & MITRA, S. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.20.13250 · Cited by 13 · see citing works
Increasing DNA repair capacity in bone marrow by gene transfer as a prospective tool in cancer therapy.
Kleibl, K., & Margison, G. P. (1998) · PubMed · Cited by 12 · see citing works
O6-Alkylguanine-DNA Alkyltransferase Inactivation by Ester Prodrugs of O6-Benzylguanine Derivatives and their Rate of Hydrolysis by Cellular Esterases
Dolan, M. E., Roy, S. K., Garbiras, B. J., Helft, P. R., Paras, P. R., Chae, M.-Y., Moschel, R. C., & Pegg, A. E. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00047-1 · Cited by 12 · see citing works
Self-citation
Organization and Expression of the Mouse Gene for DNA Repair Methyltransferase
Iwakuma, T., SHIRAISHI, A., FUKUHARA, M., Kawate, H., & Sekiguchi, M. (1996) · DNA and Cell Biology · doi:10.1089/dna.1996.15.863 · Cited by 11 · see citing works
Substrate Specificity of Human O6-Methylguanine-DNA Methyltransferase for O6-Benzylguanine Derivatives in Oligodeoxynucleotides
Terashima, I., Kawate, H., Sakumi, K., Sekiguchi, M., & Kohda, K. (1997) · Chemical Research in Toxicology · doi:10.1021/tx9700580 · Cited by 11 · see citing works
Targeting of O6-methylguanine-DNA methyltransferase (MGMT) activity by antimessenger oligonucleotide sensitizes CHO/Mex+ transfected cells to mitozolomide
Citti, L., Boldrini, L., Preuss, I., Kaina, B., Mariani, L., & Rainaldi, G. (1996) · Carcinogenesis · doi:10.1093/carcin/17.1.25 · Cited by 9 · see citing works
Leukocyte O6-alkylguanine-DNA alkyltransferase from human donors is uniformly sensitive to O6-benzylguanine.
Gerson, S. L., Schupp, J., Liu, L., Pegg, A. E., & Srinivasen, S. (1999) · PubMed · Cited by 8 · see citing works
Self-citation
Recombinant human O6-alkylguanine-DNA alkyltransferase (AGT), Cys145-alkylated AGT and Cys145→Met145 mutant AGT: comparison by isoelectric focusing, CD and time-resolved fluorescence spectroscopy
Federwisch, M., Hassiepen, U., Bender, K., Dewor, M., Rajewsky, M. F., & Wollmer, A. (1997) · Biochemical Journal · doi:10.1042/bj3240321 · Cited by 8 · see citing works
Melanoma-cell toxicity of cystemustine combined with O6-benzyl-N2-acetylguanosine
Buchdahl, C., Rolhion, C., Glasser, A.-L., Débiton, E., Mounetou, E., Madelmont, J., & Laval, F. (1998) · Melanoma Research · doi:10.1097/00008390-199804000-00004 · Cited by 7 · see citing works
O6-Alkylguanine-DNA alkyltransferase in normal colon tissue and colon cancer.
White, A., Kibitel, J. T., Garcia, Y., Belanich, M., Yarosh, D. B., Wideroff, J., Levin, L., Held, D., Fuchs, A., & Citron, M. L. (1997) · PubMed · Cited by 7 · see citing works

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22 of the 167 references couldn’t be matched to a known paper.

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Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality
Sletten, E. M., & Bertozzi, C. R. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200900942 · Cited by 3,165 · see citing works
A general method for the covalent labeling of fusion proteins with small molecules in vivo
Keppler, A., Gendreizig, S., Gronemeyer, T., Pick, H. M., Vogel, H., & Johnsson, K. (2002) · Nature Biotechnology · doi:10.1038/nbt765 · Cited by 1,964 · see citing works
Genetic Pathways to Primary and Secondary Glioblastoma
Ohgaki, H., & Kleihues, P. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070011 · Cited by 1,487 · see citing works
“Various adducts at this position are substrates for repair by MGMT.(82) Such adducts typically result from exposure to N-nitrosamides and related alkylating agents that cause brain tumors in rats,(83) but there is currently no evidence indicating that alkylating carcinogens are involved in the etiology of human brain…”
Background
Population-Based Studies on Incidence, Survival Rates, and Genetic Alterations in Astrocytic and Oligodendroglial Gliomas
Ohgaki, H., & Kleihues, P. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/64.6.479 · Cited by 1,382 · see citing works
“DNA methylation may be caused by N-nitroso compounds in food or tobacco (21, 64), and through nonenzymatic methylation by S-adenosylmethionine (SAM) (65).”
BackgroundInfluential
MGMT: its role in cancer aetiology and cancer therapeutics
Gerson, S. L. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1319 · Cited by 817 · see citing works
“AGT repairs O 6 -AG in both open chromatin during transcription and replication, and in resting, condensed DN”
Background
Correlation of O 6 -Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity
Hegi, M. E., Liu, L., Herman, J. G., Stupp, R., Wick, W., Weller, M., Mehta, M. P., & Gilbert, M. R. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.11.5964 · Cited by 811 · see citing works
Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide
Hegi, M. E., Diserens, A., Godard, S., Dietrich, P.-Y., Regli, L., Ostermann, S., Otten, P., van Melle, G., de Tribolet, N., & Stupp, R. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0384 · Cited by 782 · see citing works
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Weller, M., Stupp, R., Reifenberger, G., Brandes, A. A., van den Bent, M. J., Wick, W., & Hegi, M. E. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.197 · Cited by 779 · see citing works
“MGMT rapidly reverses alkylation, including methylation, at the O(6) position of guanine by transferring the alkyl group to the active site of the enzyme.(3) Although O(6)-alkylguanine is not the main lesion induced by alkylating agents, it seems to be the most cytotoxic one.”
Background
MGMT: Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents
Kaina, B., Christmann, M., Naumann, S. C., & Roos, W. P. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.03.008 · Cited by 662 · see citing works
Alkylation damage in DNA and RNA—repair mechanisms and medical significance
Drabløs, F., Feyzi, E., Aas, P. A., Vågbø, C. B., Kavli, B., Bratlie, M. S., Peña-Dı́az, J., Otterlei, M., Slupphaug, G., & Krokan, H. E. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.05.004 · Cited by 645 · see citing works
“AGT prefers lesions in double-stranded B-DNA and repair Z-DNA, DNA:RNA hybrids and single-stranded DNA more slowly (reviewed in[54]).”
BackgroundInfluential
AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli
Falnes, P. Ø., Johansen, R., & Seeberg, E. C. (2002) · Nature · doi:10.1038/nature01048 · Cited by 617 · see citing works
“In the transferase reaction the alkyl group is transferred from the DNA to the transferase itself, which is then consumed during repair in a stoichiometric fashion (reviewed in ref”
Method
Bioorthogonale Chemie – oder: in einem Meer aus Funktionalität nach Selektivität fischen
Sletten, E. M., & Bertozzi, C. R. (2009) · Angewandte Chemie · doi:10.1002/ange.200900942 · Cited by 564 · see citing works
Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention
Hecht, S. S. (2002) · The Lancet Oncology · doi:10.1016/s1470-2045(02)00815-x · Cited by 536 · see citing works
MGMT Promoter Methylation and Field Defect in Sporadic Colorectal Cancer
Shen, L., Kondo, Y., Rosner, G. L., Xiao, L., Hernandez, N., Vilaythong, J. N., Houlihan, P., Krouse, R. S., Prasad, A. R., Einspahr, J. G., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji275 · Cited by 492 · see citing works
Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine
Roos, W. P., Batista, L. F. Z., Naumann, S. C., Wick, W., Weller, M., Menck, C. F. M., & Kaina, B. (2006) · Oncogene · doi:10.1038/sj.onc.1209785 · Cited by 499 · see citing works
“Guanine in DNA is thereby restored and MGMT gets inactivated (for a review see Pegg, 2000).”
Background
Formation and Repair of Interstrand Cross-Links in DNA
Noll, D. M., Mason, T. M., & Miller, P. S. (2005) · Chemical Reviews · doi:10.1021/cr040478b · Cited by 485 · see citing works
Methylating Agents and DNA Repair Responses: Methylated Bases and Sources of Strand Breaks
Wyatt, M. D., & Pittman, D. L. (2006) · Chemical Research in Toxicology · doi:10.1021/tx060164e · Cited by 470 · see citing works
Genetic alterations and signaling pathways in the evolution of gliomas
Ohgaki, H., & Kleihues, P. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01308.x · Cited by 452 · see citing works
“DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from O6-methylguanine,( 77 ) a promutagenic DNA adduct that causes G:C fi A:T mutations during DNA replication.(78,79) Loss or reduction of MGMT activity due to promoter methylation is frequent (40‐57%) in glioblastoma…”
Background
Labeling of fusion proteins with synthetic fluorophores in live cells
Keppler, A., Pick, H. M., Arrivoli, C., Vogel, H., & Johnsson, K. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401923101 · Cited by 443 · see citing works
Epidemiology of Brain Tumors
Ohgaki, H. (2008) · Methods in molecular biology · doi:10.1007/978-1-60327-492-0_14 · Cited by 423 · see citing works
Chemistry and Biology of DNA Repair
Schärer, O. D. (2003) · Angewandte Chemie International Edition · doi:10.1002/anie.200200523 · Cited by 381 · see citing works
Living Radical Polymerization as a Tool for the Synthesis of Polymer‐Protein/Peptide Bioconjugates
Nicolas, J., Mantovani, G., & Haddleton, D. M. (2007) · Macromolecular Rapid Communications · doi:10.1002/marc.200700112 · Cited by 320 · see citing works
Directed Evolution of O6-Alkylguanine-DNA Alkyltransferase for Efficient Labeling of Fusion Proteins with Small Molecules In Vivo
Juillerat, A., Gronemeyer, T., Keppler, A., Gendreizig, S., Pick, H. M., Vogel, H., & Johnsson, K. (2003) · Chemistry & Biology · doi:10.1016/s1074-5521(03)00068-1 · Cited by 313 · see citing works
Triazene compounds: Mechanism of action and related DNA repair systems
Marchesi, F., Turriziani, M., Tortorelli, G., Avvisati, G., Torino, F., & Devecchis, L. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.08.003 · Cited by 299 · see citing works
Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches
Dietlein, F., Thelen, L., & Reinhardt, H. C. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.06.003 · Cited by 280 · see citing works
CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas
Paz, M. F., Yayá, R., Rojas-Marcos, I., Reynés, G., Pollán, M., Aguirre‐Cruz, L., García-Lopez, J. L., Piquer, J., Safont, M. J., Balañá, C., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0392 · Cited by 260 · see citing works
“However, the toxicity of alkylating agents is reduced in the presence of O(6)-methylguanine DNA methyltransferase (MGMT) by rapidly reversing the formation of adducts at the O(6) position of guanine (2, 3), thereby averting the formation of lethal cross-links.”
Background
Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C -> A:T mutations of the TP53 tumor suppressor gene
Nakamura, M. (2001) · Carcinogenesis · doi:10.1093/carcin/22.10.1715 · Cited by 248 · see citing works
“1717 substrates for repair by MGMT ( 12 ).”
BackgroundInfluential
Targeted Modulation of MGMT: Clinical Implications
Liu, L., & Gerson, S. L. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2543 · Cited by 245 · see citing works
O6-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry
Christmann, M., Verbeek, B., Roos, W. P., & Kaina, B. (2011) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2011.06.002 · Cited by 242 · see citing works
Optimization of Quantitative MGMT Promoter Methylation Analysis Using Pyrosequencing and Combined Bisulfite Restriction Analysis
Mikeska, T., Bock, C., El‐Maarri, O., Hübner, A., Ehrentraut, D., Schramm, J., Felsberg, J., Kahl, P., Büttner, R., Pietsch, T., et al. (2007) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2007.060167 · Cited by 241 · see citing works
Glioblastoma Multiforme Therapy and Mechanisms of Resistance
Ramirez, Y. P., Weatherbee, J. L., Wheelhouse, R. T., & Ross, A. H. (2013) · Pharmaceuticals · doi:10.3390/ph6121475 · Cited by 236 · see citing works
“O6-BG is a small-molecule pseudosubstrate that transfers a benzyl group to the MGMT active site cysteine 145 residue, thereby, inactivating MGMT and preventing removal of methyl groups from the DNA [26].”
Background
Genetic pathways to glioblastomas
Ohgaki, H. (2005) · Neuropathology · doi:10.1111/j.1440-1789.2004.00600.x · Cited by 235 · see citing works
“A great variety of adducts at this position have been shown to be substrates for repair by MGMT.(62) Such adducts typically result from exposure to N-nitrosamides and related alkylating agents that cause brain tumors in rats(63) but it remains to be shown”
Background
Multifaceted Roles of Alkyltransferase and Related Proteins in DNA Repair, DNA Damage, Resistance to Chemotherapy, and Research Tools
Pegg, A. E. (2011) · Chemical Research in Toxicology · doi:10.1021/tx200031q · Cited by 223 · see citing works
Self-citation
The intricate structural chemistry of base excision repair machinery: Implications for DNA damage recognition, removal, and repair
Hitomi, K., Iwai, S., & Tainer, J. A. (2007) · DNA Repair · doi:10.1016/j.dnarep.2006.10.004 · Cited by 220 · see citing works
“[73] A.”
Background
Protein Engineering For Directed Immobilization
Redeker, E. S., Ta, D. T., Cortens, D., Billen, B., Guedens, W., & Adriaensens, P. (2013) · Bioconjugate Chemistry · doi:10.1021/bc4002823 · Cited by 217 · see citing works
Direct Reversal of DNA Alkylation Damage
Mishina, Y., Duguid, E. M., & He, C. (2006) · Chemical Reviews · doi:10.1021/cr0404702 · Cited by 208 · see citing works
Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma
Vlassenbroeck, I., Califice, S., Diserens, A., Migliavacca, E., Straub, J., Stefano, I. D., Moreau, F., Hamou, M., Renard, I., Delorenzi, M., et al. (2008) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2008.070169 · Cited by 198 · see citing works
O6‐alkylguanine‐DNA alkyltransferase: Role in carcinogenesis and chemotherapy
Margison, G. P., & Santibanez‐Koref, M. (2002) · BioEssays · doi:10.1002/bies.10063 · Cited by 188 · see citing works
Variability and regulation of O6-alkylguanine-DNA alkyltransferase
Margison, G. P. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg005 · Cited by 182 · see citing works
Alkylpurine–DNA–N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients
Agnihotri, S., Gajadhar, A. S., Ternamian, C., Gorlia, T., Alfaro-Munoz, K. D., Mischel, P. S., Kelly, J. R., McGown, G., Thorncroft, M. R., Carlson, B. L., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59334 · Cited by 172 · see citing works
Personalized treatment strategies in glioblastoma: MGMT promoter methylation status
Thon, N., Kreth, S., & Kreth, F. W. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s50208 · Cited by 171 · see citing works
Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo
Rocha, C. R. R., Garcia, C. C. M., Vieira, D. B., Quinet, A., de Andrade-Lima, L. C., Munford, V., Belizário, J. E., & Menck, C. F. M. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.465 · Cited by 163 · see citing works
“As a consequence, the MGMT enzyme has a critical role in determining TMZ resistance; therefore, methylation of the promoter of theMGMT gene, which reduces its expression, is considered to be an important biomarker for drug responsiveness.(30) In fact, Stupp et al.”
Background
DNA methylation based biomarkers: Practical considerations and applications
Kit, A. H., Nielsen, H. M., & Tost, J. (2012) · Biochimie · doi:10.1016/j.biochi.2012.07.014 · Cited by 160 · see citing works
Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide
Bobustuc, G. C., Baker, C. H., Limaye, A., Jenkins, W. D., Pearl, G. S., Avgeropoulos, N. G., & Konduri, S. D. (2010) · Neuro-Oncology · doi:10.1093/neuonc/noq044 · Cited by 156 · see citing works
The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress.
Silber, J. R., Bobola, M. S., Blank, A., Schoeler, K. D., Haroldson, P. D., Huynh, M. B., & Kolstoe, D. D. (2002) · PubMed · Cited by 149 · see citing works
Prognostic Value of Three Different Methods of MGMT Promoter Methylation Analysis in a Prospective Trial on Newly Diagnosed Glioblastoma
Christians, A., Hartmann, C. J., Benner, A., Meyer, J., von Deimling, A., Weller, M., Wick, W., & Weiler, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033449 · Cited by 146 · see citing works
Arylamine N-acetyltransferases: From Structure to Function
Sim, E., Walters, K. J., & Boukouvala, S. (2008) · Drug Metabolism Reviews · doi:10.1080/03602530802186603 · Cited by 144 · see citing works
“Alkyltransferases are unable to dealkylate themselves and, despite being stable prior to their alkylation, disappear rapidly from cells treated with DNA-alkylating agents or O6-benzylguanine (reviewed in Pegg, 2000).”
Background
Aberrant Promoter Methylation of p16 and MGMT Genes in Lung Tumors from Smoking and Never-Smoking Lung Cancer Patients
Liu, Y., Qing Lan, B., Siegfried, J. M., Luketich, J. D., & Keohavong, P. (2006) · Neoplasia · doi:10.1593/neo.05586 · Cited by 140 · see citing works
“protein itself in an autoinactivating reaction [ 16 ].”
Background
BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability
Skórski, T. (2002) · Oncogene · doi:10.1038/sj.onc.1206087 · Cited by 136 · see citing works
Visualizing and Manipulating Biological Processes by Using HaloTag and SNAP‐Tag Technologies
Hoelzel, C. A., & Zhang, X. (2020) · ChemBioChem · doi:10.1002/cbic.202000037 · Cited by 136 · see citing works
DNA repair and cancer stem-like cells – Potential partners in glioma drug resistance?
Johannessen, T.-C. A., Bjerkvig, R., & Tysnes, B. B. (2008) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2008.03.125 · Cited by 132 · see citing works
Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas
Watanabe, T., Nakamura, M., Kros, J. M., Burkhard, C., Yonekawa, Y., Kleihues, P., & Ohgaki, H. (2001) · Acta Neuropathologica · doi:10.1007/s004010100464 · Cited by 134 · see citing works
“MGMT plays an important role in modulating the chemosensitivity of tumour cells to alkylating agents [ 33 ], since it removes alkyl groups from the O 6 position of guanine; O 6 -alkylguanine represents a crucial DNA adduct produced by chemotherapeutic agents.”
Background
Flipping of alkylated DNA damage bridges base and nucleotide excision repair
Tubbs, J. L., Latypov, V., Kanugula, S., Butt, A., Melikishvili, M., Kraehenbuehl, R., Fleck, O., Marriott, A. S., Watson, A. J., Verbeek, B., et al. (2009) · Nature · doi:10.1038/nature08076 · Cited by 132 · see citing works
Self-citation
Who's on first in the cellular response to DNA damage?
Cline, S. D., & Hanawalt, P. C. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1101 · Cited by 129 · see citing works
“The O 6 -alkylguanine alkyltransferase catalyses the efficient transfer of alkyl substituents — which range in size from methyl to benzyl groups — from the O 6 of guanine to its own active-site cysteine residu”
Background
Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps
Kim, Y. H., Kakar, S., Cun, L., Deng, G., & Kim, Y. S. (2008) · International Journal of Cancer · doi:10.1002/ijc.23840 · Cited by 120 · see citing works
Contribution of ATM and ATR to the Resistance of Glioblastoma and Malignant Melanoma Cells to the Methylating Anticancer Drug Temozolomide
Eich, M., Roos, W. P., Nikolova, T., & Kaina, B. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0136 · Cited by 119 · see citing works
Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage
Paranjpe, A., Zhang, R., Ali‐Osman, F., Bobustuc, G. C., & Srivenugopal, K. S. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt366 · Cited by 118 · see citing works
Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new targets for the prevention of acquired MDR.
Shain, K. H., & Dalton, W. S. (2001) · PubMed · Cited by 117 · see citing works
Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells
Taverna, P., Liu, L., Hwang, H.-S., Hanson, A. J., Kinsella, T. J., & Gerson, S. L. (2001) · Mutation Research/DNA Repair · doi:10.1016/s0921-8777(01)00076-3 · Cited by 116 · see citing works
O6-Methylguanine-DNA methyltransferase in glioma therapy: Promise and problems
Silber, J. R., Bobola, M. S., Blank, A., & Chamberlain, M. C. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2011.12.004 · Cited by 115 · see citing works
Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: One step forward, and one step back?
Combs, S. E., Rieken, S., Wick, W., Abdollahi, A., von Deimling, A., Debus, J., & Hartmann, C. J. (2011) · Radiation Oncology · doi:10.1186/1748-717x-6-115 · Cited by 112 · see citing works
“The O6-methylguanine-DNA-methyltransferase (MGMT) gene encodes MGMT, a protein with DNA repair activity, which removes alkyl groups from several residues, of which the O6-position of guanine might be most relevant for the action of an extensively used chemotherapeutic drug, temozolomide, by an irreversible transfer of…”
Background
Promoter Methylation and Polymorphisms of the MGMT Gene in Glioblastomas: A Population-Based Study
Zawlik, I., Vaccarella, S., Kita, D., Mittelbronn, M. G. A., Franceschi, S., & Ohgaki, H. (2008) · Neuroepidemiology · doi:10.1159/000170088 · Cited by 111 · see citing works
“O 6 -methylguanine-DNA methyltransferase(MGMT) is a repair protein that specifically removes promutagenic alkyl groups from O 6 - methylguanine [”
Background
Analysis of Protein Turnover by Quantitative SNAP‐Based Pulse‐Chase Imaging
Bodor, D. L., Rodríguez, M. G., Moreno, N., & Jansen, L. E. T. (2012) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0808s55 · Cited by 109 · see citing works
“It acts as a suicide enzyme that catalyzes a covalent binding reaction between itself and the alkyl group that is removed from guanines, thereby restoring DNA integrity but inactivating its own catalytic activity (Pegg, 2000).”
Background
The prognostic value of MGMT promoter methylation in Glioblastoma multiforme: a meta-analysis
Zhang, K., Wang, X., Zhou, B., & Zhang, L. (2013) · Familial Cancer · doi:10.1007/s10689-013-9607-1 · Cited by 111 · see citing works
“The O-methylguanine-DNA methyltransferase (MGMT) gene encodes a ubiquitously expressed suicide DNA repair enzyme that counteracts the normally lethal effects of alkylating agents by removing alkyl adducts from the O-position of guanine [6].”
Background
Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O6-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs
Roos, W. P., Nikolova, T., Quirós, S., Naumann, S. C., Kiedron, O., Zdzienicka, M. Z., & Kaina, B. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.09.003 · Cited by 106 · see citing works
Predicting drug response and toxicity based on gene polymorphisms
Robert, J., Morvan, V. L., Smith, D. M., Pourquier, P., & Bonnet, J. (2005) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.01.005 · Cited by 106 · see citing works
DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways
Fahrer, J., & Christmann, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054684 · Cited by 110 · see citing works
Methylated genes as new cancer biomarkers
Duffy, M. J., Napieralski, R., Martens, J. W. M., Span, P. N., Spyratos, F., Sweep, F. C. G. J., Brünner, N., Foekens, J. A., & Schmitt, M. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.12.008 · Cited by 105 · see citing works
Formation and Repair of Tobacco Carcinogen‐Derived Bulky DNA Adducts
Hang, B. (2010) · Journal of Nucleic Acids · doi:10.4061/2010/709521 · Cited by 103 · see citing works
“These examples involve repair systems including at least NER, BER, NIR, and AGT [268].”
BackgroundInfluential
Inactivation and degradation of O(6)-alkylguanine-DNA alkyltransferase after reaction with nitric oxide.
Liu, L., Xu‐Welliver, M., Kanugula, S., & Pegg, A. E. (2002) · PubMed · Cited by 101 · see citing works
Self-citation
Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53
Naumann, S. C., Roos, W. P., Jöst, E., Belohlavek, C., Lennerz, V., Schmidt, C., Christmann, M., & Kaina, B. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604856 · Cited by 101 · see citing works
“It repairs the pre-toxic DNA lesion O6-methylguanine (O6MeG) by transfer of the methyl group from guanine to an own cysteine residue (Pegg, 2000).”
Background
Protective Effect of Red Beetroot against Carbon Tetrachloride- and N-Nitrosodiethylamine-Induced Oxidative Stress in Rats
Kujawska, M., Ignatowicz, E., Murias, M., Ewertowska, M., Mikołajczyk, K., & Jodynis‐Liebert, J. (2009) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf803315d · Cited by 102 · see citing works
Adding value to fusion proteins through covalent labelling
Gronemeyer, T., Godin, G., & Johnsson, K. (2005) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2005.06.001 · Cited by 99 · see citing works
Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma
Augustine, C. K., Yoo, J. S., Potti, A., Yoshimoto, Y., Zipfel, P. A., Friedman, H. S., Nevins, J. R., Ali‐Osman, F., & Tyler, D. S. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1916 · Cited by 98 · see citing works
Chemotherapy in glioma
Taal, W., Bromberg, J. E. C., & van den Bent, M. J. (2015) · CNS Oncology · doi:10.2217/cns.15.2 · Cited by 96 · see citing works
The Structure of the Human AGT Protein Bound to DNA and its Implications for Damage Detection
Duguid, E. M., Rice, P. A., & He, C. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.05.028 · Cited by 96 · see citing works
The Selectivity and Inhibition of AlkB
Welford, R. W. D., Schlemminger, I., McNeill, L. A., Hewitson, K. S., & Schofield, C. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211058200 · Cited by 96 · see citing works
Epigenetics and Precision Oncology
Werner, R. J., Kelly, A. D., & Issa, J. J. (2017) · The Cancer Journal · doi:10.1097/ppo.0000000000000281 · Cited by 94 · see citing works
“O(6)-methylguanineDNAmethyltransferase is a ubiquitously expressed DNA repair enzyme that removes alkyl adducts from the O(6) position of guanine.(60) The presence of O(6)-alkylated guanine in DNA leads to doublestrand breaks resulting in apoptosis and cell death.”
Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy
Sabharwal, A., & Middleton, M. R. (2006) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2006.03.011 · Cited by 94 · see citing works
Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy.
Rabik, C., Njoku, M., & Dolan, M. (2006) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2006.03.004 · Cited by 92 · see citing works
p53-Mediated down-regulation of the human DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) via interaction with Sp1 transcription factor.
Bocangel, D., Sengupta, S., MITRA, S. P., & Bhakat, K. K. (2009) · PubMed · Cited by 94 · see citing works
Chemical tags: Applications in live cell fluorescence imaging
Wombacher, R., & Cornish, V. W. (2011) · Journal of Biophotonics · doi:10.1002/jbio.201100018 · Cited by 91 · see citing works
Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia.
Rossi, D., Capello, D., Gloghini, A., Franceschetti, S., Paulli, M., Bhatia, K. G., Saglio, G. N., Vitolo, U., Pileri, S. A., Esteller, M., et al. (2004) · PubMed · Cited by 90 · see citing works
Epigenetic silencing of O6 -methylguanine DNA methyltransferase gene in NiS-transformed cells
Ji, W., Yang, L., Yu, L., Yuan, J., Hu, D., Zhang, W., Yang, J., Pang, Y., Li, W., Lü, J., et al. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn012 · Cited by 88 · see citing works
Enforced expression of wild-type p53 curtails the transcription of the O(6)-methylguanine-DNA methyltransferase gene in human tumor cells and enhances their sensitivity to alkylating agents.
Srivenugopal, K. S., Shou, J., Mullapudi, S., Lang, F. F., Rao, J. S., & Ali‐Osman, F. (2001) · PubMed · Cited by 88 · see citing works
The DNA repair protein, O6-Methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein
Srivenugopal, K. S., & Ali‐Osman, F. (2002) · Oncogene · doi:10.1038/sj.onc.1205762 · Cited by 87 · see citing works
“…reserved 0950 – 9232/02 $25.00 www.nature.com/onc mechanism in which the alkyl groups bound to the O6 position of guanine are transferred to a cysteine in its active site; this reaction results in the direct restoration of the normal guanine structure and self-inactivation of the MGMT (Pegg, 2000).”
BackgroundInfluential
Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair
Roos, W. P., Christmann, M., Fraser, S. T., & Kaina, B. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402136 · Cited by 86 · see citing works
Engineering Substrate Specificity of O6‐Alkylguanine‐DNA Alkyltransferase for Specific Protein Labeling in Living Cells
Juillerat, A., Heinis, C., Sielaff, I., Barnikow, J., Jaccard, H., Kunz, B., Terskikh, A. V., & Johnsson, K. (2005) · ChemBioChem · doi:10.1002/cbic.200400431 · Cited by 86 · see citing works
Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation
Pietrantonio, F., Perrone, F., de Braud, F., Castano, A., Maggi, C., Bossi, I., Gevorgyan, A., Biondani, P., Pacifici, M., Busico, A., et al. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt547 · Cited by 86 · see citing works
Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres
Sciuscio, D., Diserens, A., Dommelen, K. V., Martinet, D., Jones, G., Janzer, R.-C., Pollo, C., Hamou, M., Kaina, B., Stupp, R., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1931 · Cited by 84 · see citing works
Proteomic Analysis of DNA−Protein Cross-Linking by Antitumor Nitrogen Mustards
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Authors: Pegg, A. E.
Affiliations: Pennsylvania State University (US)
Corresponding author: Pegg, Anthony E
Venue: Mutation Research/Reviews in Mutation Research
Publisher: Elsevier BV
Published: 2000-04
Volume: 462
Issue: 2-3
Pages: 83-100
ISSN: 1383-5742 (ISSN-L)
DOI: 10.1016/s1383-5742(00)00017-x
OpenAlex: W1999549596
Cited by: 576
References: 167
Citations by year: 2026: 4 · 2025: 11 · 2024: 16 · 2023: 12 · 2022: 11 · 2021: 10 · 2020: 15 · 2019: 17 · 2018: 13 · 2017: 14 · 2016: 16 · 2015: 21 · 2014: 30 · 2013: 36 · 2012: 26
FWCI: 1.69
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Mutation Research/Reviews in Mutation Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA57725, CA-18137, R01CA071976, CA 71976)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords: O6-alkylguanine, alkyltransferase, DNA repair, O6-methylguanine, O6-benzylguanine, alkylating agents, ubiquitin-proteasome degradation, promoter methylation, gene silencing, p53, temozolomide resistance, transgenic mice, myelosuppression
MeSH terms: Animals, DNA Repair, Guanine, Humans, DNA Adducts, Alkyl and Aryl Transferases

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Repair of O6-alkylguanine by alkyltransferases

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