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

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Repair of O6-alkylguanine by alkyltransferases

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

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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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Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia.
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Ekim, M., Caner, V., Büyükpınarbaşılı, N., Tepeli, E., Elmas, L., & Bağcı, G. (2011) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2010.0211 · Cited by 12
“It has been reported that the frequency of promoter methylation of MGMT was increased in a variety of human cancers, including lung cancer (Pegg, 2000; Esteller, 2007; Jacinto and Esteller, 2007).”
O6-methylguanine-DNA methyltransferase (MGMT): Can function explain a suicidal mechanism?
Gouws, C., & Pretorius, P. J. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2011.07.055 · Cited by 12
Endocrine disrupting chemicals modulate expression of O6-methylguanine DNA methyltransferase (O6-MGMT) gene in the hermaphroditic fish, Kryptolebias marmoratus
Rhee, J., Kim, R., Chang, H., Lee, J., Lee, Y.-M., & Lee, J.-S. (2010) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2010.10.005 · Cited by 12
Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease
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Matsuda, S., Mafune, A., Kohda, N., Hama, T., & Urashima, M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231932 · Cited by 12
Genomic Space of MGMT in Human Glioma Revisited: Novel Motifs, Regulatory RNAs, NRF1, 2, and CTCF Involvement in Gene Expression
Al-Obaide, M. A. I., Arutla, V., Bacolod, M. D., Wang, W., Zhang, R., & Srivenugopal, K. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052492 · Cited by 12
“Both the antimutagenic and drug resistance properties conferred by MGMT derive from its ability to remove the alkyl groups from the O6-position in the DNA to cysteine 145 at the active site in a unique suicidal reaction [1,2,5].”
Background
Differential competitive resistance to methylating versus chloroethylating agents among five O6-alkylguanine DNA alkyltransferases in human hematopoietic cells
Fontes, A. M., Davis, B. M., Encell, L. P., Lingas, K. T., Covas, D. T., Zago, M. A., Loeb, L. A., Pegg, A. E., & Gerson, S. L. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0236 · Cited by 12
“because large numbers of adducts are formed, and removal of most of these adducts is required to protect the cell (27).”
BackgroundSelf-citation
Chemosensitivity of conjunctival melanoma cell lines to single chemotherapeutic agents and combinations
Westekemper, H., Freistuehler, M., Anastassiou, G., Nareyeck, G., Bornfeld, N., Steuhl, K., Scheulen, M. E., & Hilger, R. A. (2012) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2011-300686 · Cited by 12
“DNA repair by the O6-methylguanine-DNA methyltransferase (MGMT) is involved in drug resistance to methylating drugs and therapeutic agents with similar characteristics.(29) We have not examined the underlying mechanism of the resistance of the conjunctival melanoma cell lines to fotemustine, but it may be connected wi…”
Background
A Convenient Procedure for the Synthesis of O6-Benzylguanine Derivatives by Phase Transfer Catalysis
Liu, X., Zheng, Q., Hutchins, G. D., Fei, X., Erickson, L. C., Miller, K. D., Mock, B. H., Glick‐Wilson, B. E., Winkle, W. L., Stone, K. L., et al. (2003) · Synthetic Communications · doi:10.1081/scc-120016358 · Cited by 12
Mass Spectrometry Based Approach to Study the Kinetics of O6-Alkylguanine DNA Alkyltransferase-Mediated Repair of O6-Pyridyloxobutyl-2′-deoxyguanosine Adducts in DNA
Kotandeniya, D., Murphy, D., Seneviratne, U. I., Guza, R., Pegg, A. E., Kanugula, S., & Tretyakova, N. Y. (2011) · Chemical Research in Toxicology · doi:10.1021/tx2002993 · Cited by 11
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DRUG RESISTANCE PATHWAYS AS TARGETS
Tomida, A., & Tsuruo, T. (2002) · Elsevier eBooks · doi:10.1016/b978-012072651-6/50006-1 · Cited by 11
The DNA Alkylguanine DNA Alkyltransferase-2 (AGT-2) Of Caenorhabditis Elegans Is Involved In Meiosis And Early Development Under Physiological Conditions
Serpe, M., Forenza, C., Adamo, A., Russo, N., Perugino, G., Ciaramella, M., & Valenti, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-43394-1 · Cited by 11
Quantitative Proteomics Analysis Reveals Nuclear Perturbation in Human Glioma U87 Cells treated with Temozolomide
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Effect of O6‐alkylguanine‐DNA alkyltransferase on genotoxicity of epihalohydrins
Kalapila, A. G., Loktionova, N. A., & Pegg, A. E. (2009) · Environmental and Molecular Mutagenesis · doi:10.1002/em.20491 · Cited by 11
“N IH -PA A uth or M an uscript N IH -PA A uth or M an uscript (Pegg, 2000; Margison and Santibáñez-Koref, 2002; Margison et al., 2003; Tubbs et al., 2007).”
BackgroundSelf-citation
Characterisation of a P140K mutant O6‐methylguanine‐DNA‐methyltransferase (MGMT)‐expressing transgenic mouse line with drug‐selectable bone marrow
Kramer, B., Lemckert, F. A., Alexander, I. E., Gunning, P. W., & McCowage, G. B. (2006) · The Journal of Gene Medicine · doi:10.1002/jgm.937 · Cited by 11
State of the art chemotherapeutic management of pediatric brain tumors
Siegel, M. J., Finlay, J. L., & Zacharoulis, S. (2006) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.6.5.765 · Cited by 11
Enhanced DNA excision repair in CCRF-CEM cells resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, quantitated using the single cell gel electrophoresis (Comet) assay
Yamauchi, T., Kawai, Y., & Ueda, T. (2003) · Biochemical Pharmacology · doi:10.1016/s0006-2952(03)00412-x · Cited by 11
Genomic Instability and DNA Repair
Kohn, K. W., & Bohr, V. A. (2005) · Wiley eBooks · doi:10.1002/0470025077.chap07 · Cited by 11
Implications of Advances in Studies of O6-Methylguanine-DNA- Methyltransferase for Tumor Prognosis and Treatment
Chen, Y., Qu, W., Tu, J., & Qi, H. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2809197 · Cited by 10
MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression
Xu, M., Cross, C. E., Speidel, J. T., & Abdel‐Rahman, S. Z. (2016) · Cellular Oncology · doi:10.1007/s13402-016-0286-4 · Cited by 10
Cross-linking of the DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of cisplatin
Ming, X., Michaelson-Richie, E. D., Groehler, A. S., Villalta, P. W., Campbell, C., & Tretyakova, N. Y. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102840 · Cited by 10
“AGT is an important DNA repair protein that removes promutagenic DNA O6-alkylguanine lesions formed as a result of exposure to chemotherapeutic drugs and environmental toxins [36].”
Background
Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In Vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide
Eda, T., Okada, M., Ogura, R., Tsukamoto, Y., Kanemaru, Y., Watanabe, J., On, J., Aoki, H., Oishi, M., Takei, N., et al. (2022) · Cancers · doi:10.3390/cancers14030770 · Cited by 10
“In TMZ-based chemotherapy, where DNA mismatch and subsequent apoptosis occurs, resistance has been associated with MGMT expression [40].”
Background
Hsp27 (HSPB1): a possible surrogate molecular marker for loss of heterozygosity (LOH) of chromosome 1p in oligodendrogliomas but not in astrocytomas
Castro, G. N., Cayado-Gutiérrez, N., Moncalero, V. L., Lima, P., Angelis, R. L. D., Chávez, V., Cuello-Carrión, F. D., & Ciocca, D. R. (2012) · Cell Stress and Chaperones · doi:10.1007/s12192-012-0350-6 · Cited by 10
“MGMT expression has a central role in resistance to alkylating agents such as temozolomide, and it is an ideal potential target for biochemical modulation of drug resistance (Bignami et al. 2000; Pegg 2000; Gerson 2004).”
Background
Methylation of estrogen receptor 1 in colorectal adenomas is not age‐dependent, but is correlated with K‐ras mutation
Horii, J., Hiraoka, S., Kato, J., Saito, S., Harada, K., Fujita, H., Kaji, E., & Yamamoto, K. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01140.x · Cited by 10
Evolutionary pattern of four representative DNA repair proteins across six model organisms: an in silico analysis
Kanchan, S., Mehrotra, R., & Chowdhury, S. (2014) · Network Modeling Analysis in Health Informatics and Bioinformatics · doi:10.1007/s13721-014-0070-1 · Cited by 9
“Our analysis has also identified helix-turn-helix AraC domain and Ada_Zn_binding domains within MGMT protein of E. coli which is deleted during course of evolution.”
Influential
Direct Reversal Repair in Mammalian Cells
Ahmad, A., Nay, S. L., & O'Connor, T. R. (2015) · InTech eBooks · doi:10.5772/60037 · Cited by 8
The regulation of a variability of somatic mammalian cell genome under the influence of exogeneous biological factors
Лукаш, Л. Л. (2004) · Biopolymers and Cell · doi:10.7124/bc.000697 · Cited by 9
Target-mediated consecutive endonuclease reactions for specific and sensitive homogeneous fluorescence assay of O6-methylguanine-DNA methyltransferase
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Lesion-specific DNA-binding and repair activities of human O6-alkylguanine DNA alkyltransferase
Melikishvili, M., & Fried, M. G. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks674 · Cited by 9
Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients
Cellarier, E., Terret, C., Labarre, P., Ouabdesselam, R., Curé, H., Marchenay, C., Maurizis, J. C., Madelmont, J., Chollet, P. J. M., & Armand, J. (2002) · Annals of Oncology · doi:10.1093/annonc/mdf098 · Cited by 9
Association of the Promoter Methylation and the rs12917 Polymorphism of MGMT with Formation of DNA Bulky Adducts and the Risk of Lung Cancer in Mexican Mestizo Population
Martínez‐Ramírez, O. C., Pérez–Morales, R., Hernández, C. C., Gonsebatt, M. E., Casas-Ávila, L., Valdés‐Flores, M., Petrosyan, P., de León-Suárez, V. P., & Rubio, J. (2019) · DNA and Cell Biology · doi:10.1089/dna.2018.4526 · Cited by 9
“…7-methyguanine and O 6 -methylguanine (MeG), this being one of the promutagenic DNA adducts that causes [G:C]A:T mutations during DNA replication (Kaina et al. , 2007; Ensminger et al. , 2014), MeG can be removed only by the enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) (Pegg, 2000).”
ETHANOL MODULATES RAT HEPATIC DNA REPAIR FUNCTIONS
Navasumrit, P. (2001) · Alcohol and Alcoholism · doi:10.1093/alcalc/36.5.369 · Cited by 9
Silence Is Golden: Gene Hypermethylation and Survival in Large-Cell Lymphoma
Dolan, M. E. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.1.6 · Cited by 9
“MGMT is a unique protein that removes O6-guanine adducts from DNA, thereby restoring the original DNA in a single step (5, 6 ).”
Background
Kinetics of O6-Pyridyloxobutyl-2′-deoxyguanosine Repair by Human O6-alkylguanine DNA Alkyltransferase
Kotandeniya, D., Murphy, D., Yan, S., Park, S., Seneviratne, U. I., Koopmeiners, J. S., Pegg, A. E., Kanugula, S., Kassie, F., & Tretyakova, N. Y. (2013) · Biochemistry · doi:10.1021/bi4004952 · Cited by 8
Self-citation
Fluorescence determination of the activity of O6-methylguanine-DNA methyltransferase based on the activation of restriction endonuclease and the use of graphene oxide
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The effectiveness of the O6-alkylguanine-DNA alkyltransferase encoded by the ogtST gene from S. typhimurium in protection against alkylating drugs, resistance to O6-benzylguanine and sensitisation to dibromoalkane genotoxicity
Abril, N., Luque-Romero, F. L., Yamada, M., Nohmi, T., & Pueyo, C. (2001) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/s1383-5718(01)00235-2 · Cited by 8
The Role of Surrogate Markers in the Clinical Development of Antiretroviral Therapy: A Model for Early Evaluation of Targeted Cancer Drugs
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Is inactivation of O6-methylguanine DNA methyltransferase still a favorable prognostic factor of patients with diffuse large B-cell lymphoma in the era of R-CHOP chemotherapy?
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Temozolomide–perillyl alcohol conjugate downregulates O6-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer
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Clinical Trials Using LV-P140K-MGMT for Gliomas
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Effect of nucleotide excision repair on ENU‐induced mutation in female germ cells of Drosophila melanogaster
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“In mammals, O6-alkylguanine is repaired by the cooperative rather than the additive action of NER and the protein O6-methylguanine-DNA methyltransferase (MGMT) [Bronstein et al., 1992], which plays an important role in alkylation damage repair in all kinds of organisms [Pegg, 2000].”
Background
Synthesis of oligodeoxyribonucleotides containing a conformationally-locked anti analogue of O6-methyl-2′-deoxyguanosine and their recognition by MGMT and Atl1
Abdu, K., Aiertza, M. K., Wilkinson, O. J., Grasby, J. A., Senthong, P., Povey, A. C., Margison, G. P., & Williams, D. M. (2012) · Chemical Communications · doi:10.1039/c2cc36252j · Cited by 7

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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