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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Biosynthesis of Covalently Bound Flavin: Isolation and in Vitro Flavinylation of the Monomeric Sarcosine Oxidase Apoprotein
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“Of course, the apoprotein is not a true catalyst since it is modified during the reaction, analogous to single turnover proteins like O6-methylguanine-DNA alkyltransferases that repair alkylated DNA by transferring the alkyl group to one of their own cysteine residues (35).”
Background
Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma
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“O(6)-methylguanine in a damage reversal reaction [4].”
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“the generation of O6-MeG DNA adducts, which, if not repaired by MGMT, produce wrong pairing of bases triggering the intervention of a mismatch repair system [25,26].”
Background
O6-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke
Christmann, M., & Kaina, B. (2011) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2011.06.004 · Cited by 45
Interactions of Human O6-Alkylguanine-DNA Alkyltransferase (AGT) with Short Single-stranded DNAs
Rasimas, J. J., Kar, S. R., Pegg, A. E., & Fried, M. G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608876200 · Cited by 45
Self-citation
Imaging Genomics of Glioblastoma
Elbanan, M., Amer, A. M., Zinn, P. O., & Colen, R. R. (2014) · Neuroimaging Clinics of North America · doi:10.1016/j.nic.2014.09.010 · Cited by 45
The polymorphic human glutathione transferase T1-1, the most efficient glutathione transferase in the denitrosation and inactivation of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea
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Expression of glioma stem cell marker CD133 and O6-methylguanine-DNA methyltransferase is associated with resistance to radiotherapy in gliomas
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O6-Methylguanine DNA lesions induce an intra-S-phase arrest from which cells exit into apoptosis governed by early and late multi-pathway signaling network activation
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Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco‐Specific Nitrosamines
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“O6-Alkylguanine DNA alkyltransferase (AGT) is a suicide protein that repairs O6-alkylguanine adducts by facilitating the transfer of the alkyl group from the O6-position of guanine to a cysteine residue in the protein’s active site [35].”
Background
The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function
Blank, A., Bobola, M. S., Gold, B. I., Varadarajan, S., Kolstoe, D. D., Meade, E. H., Rabinovitch, P. S., Loeb, L. A., & Silber, J. R. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.02.003 · Cited by 43
The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer
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“…agents like TMZ, as well as chloroethylating agents such as BCNU, ACNU, and MeCCNU, thereby promoting resistance to chemotherapy using these agents [3,4,13,31,39]. hMGMT activity has also been associated with the resistance to 6-thioguanine that a medication used to treat leukemia [142].”
Background
Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice
Hansen, R. J., Nagasubramanian, R., Delaney, S. M., Samson, L. D., & Dolan, M. E. (2006) · Carcinogenesis · doi:10.1093/carcin/bgl218 · Cited by 41
“induced by both TMZ and BCNU [2,32,33], these results do not support a role for”
BackgroundResult
Chromophore-Assisted Laser Inactivation of α- and γ-Tubulin SNAP-tag Fusion Proteins inside Living Cells
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O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)
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Hepatocarcinogenesis Driven by GSNOR Deficiency Is Prevented by iNOS Inhibition
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Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis
Anisimov, V. N. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(01)00262-7 · Cited by 41
Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains
Weizman, N., Shiloh, Y., & Barzilai, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211168200 · Cited by 40
The therapeutic potential ofO6-alkylguanine DNA alkyltransferase inhibitors
Khan, O. A., & Middleton, M. R. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.10.1573 · Cited by 40
O6-(4-Bromothenyl)guanine (PaTrin-2), a novel inhibitor of O6-alkylguanine DNA alkyl-transferase, increases the inhibitory activity of temozolomide against human acute leukaemia cells in vitro
Turriziani, M., Caporaso, P., Bonmassar, L., Buccisano, F., Amadori, S., Venditti, A., Cantonetti, M., D’Atri, S., & Bonmassar, E. (2006) · Pharmacological Research · doi:10.1016/j.phrs.2005.12.001 · Cited by 39
Delayed repletion of O6-methylguanine—DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity
Hirose, Y., Kreklau, E. L., Erickson, L. C., Berger, M. S., & Pieper, R. O. (2003) · Journal of neurosurgery · doi:10.3171/jns.2003.98.3.0591 · Cited by 39
Inhibition of Telomerase Increases Resistance of Melanoma Cells to Temozolomide, but Not to Temozolomide Combined with Poly (ADP-Ribose) Polymerase Inhibitor
Tentori, L., Portarena, I., Barbarino, M., Balduzzi, A., Levati, L., Vergati, M., Biroccio, A., Gold, B. I., Lombardi, M. L., & Graziani, G. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.1.192 · Cited by 39
“…trials with TMZ are promising, the efficacy of O6-methylating agents is strongly influenced by the functional status of DNA repair systems, such as O6-alkylguanine DNA alkyltransferase (AGT), which removes the methyl adduct from the O6-position of guanine (Pegg, 2000) and mismatch repair (MR).”
Background
No-observed effect levels are associated with up-regulation of MGMT following MMS exposure
Doak, S. H., Brüsehafer, K., Dudley, E., Quick, E. L., Johnson, G. E., Newton, R. P., & Jenkins, G. J. S. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2008.09.016 · Cited by 38
PCNA-MutS -mediated binding of MutL to replicative DNA with mismatched bases to induce apoptosis in human cells
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Inhibition of O6-methylguanine-DNA methyltransferase by an alkyltransferase-like protein from Escherichia coli
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A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
Raizer, J. J., Chandler, J. P., Ferrarese, R., Grimm, S. A., Levy, R. M., Muro, K., Rosenow, J. M., Helenowski, I., RADEMAKER, A. W., Paton, M., et al. (2016) · Journal of Neuro-Oncology · doi:10.1007/s11060-016-2156-3 · Cited by 37
Development of an O6-alkylguanine–DNA alkyltransferase assay based on covalent transfer of the benzyl moiety from [benzene-3H]O6-benzylguanine to the protein
Ishiguro, K., Shyam, K., Penketh, P. G., & Sartorelli, A. C. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.08.009 · Cited by 37
“By covalently transferring the alkyl moieties to the active site cysteine, AGT restores the O(6) position of guanine to its native state and attenuates the cytotoxicity of guanine O(6)-targeting agents [6].”
Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM)
Balañá, C., Pousa, A. L., Berrocal, A., Yayá, R., Herrero, A., Garc�a, J.-L., Martín‐Broto, J., Benavides, M., Cerd�-nicol�s, M., Ballester, R., et al. (2004) · Journal of Neuro-Oncology · doi:10.1007/s11060-004-9175-1 · Cited by 37
“As the enzyme is inactivated in the process, the extent of the lesion repair is dependent on the initial levels that are present in cells and on the rate at which new AGAT is synthesized [ 8 ].”
BackgroundInfluential
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (VNP40101M): I. Direct inhibition of O 6 -alkylguanine-DNA alkyltransferase (AGT) by electrophilic species generated by decomposition
Penketh, P. G., Shyam, K., Baumann, R. P., Remack, J. S., Brent, T. P., & Sartorelli, A. C. (2004) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-003-0740-7 · Cited by 37
Chemie und Biologie der DNA‐Reparatur
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Mismatch repair defects as a cause of resistance to cytotoxic drugs
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Temozolomide induced c-Myc-mediated apoptosisviaAkt signalling in MGMT expressing glioblastoma cells
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Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours
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“Any additional DNA repair requires de novo synthesis of the protein (Pegg, 2000).”
Background
Interplay Among Hydrogen Sulfide, Nitric Oxide, Reactive Oxygen Species, and Mitochondrial DNA Oxidative Damage
Huang, D., Jing, G., Zhang, L., Chen, C., & Zhu, S. (2021) · Frontiers in Plant Science · doi:10.3389/fpls.2021.701681 · Cited by 37
“…lesion in DNA in plants, resulting in CPD splitting (Zhang M. et al., 2017); alkyltransferase could repair O(6)-methylguanine in DNA by transferring the methyl group (Pegg, 2000); and dioxygenase could also demethylate DNA methylation by oxidizing 5- methylcytosine (5-meC) (Wu et al., 2018).”
Background
Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine
Ishiguro, K., Seow, H. A., Penketh, P. G., Shyam, K., & Sartorelli, A. C. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0532 · Cited by 36
Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma
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“The DNA damage caused by temozolomide is repaired by MGMT, which is thought to be responsible for temozolomide resistance [5, 10, 24–26].”
Background
Molecular Heterogeneity of Diffuse Large B-cell Lymphoma: Implications for Disease Management and Prognosis
Rossi, D., & Gaïdano, G. (2002) · Hematology · doi:10.1080/1024533021000024058 · Cited by 35
“2) [107].”
Synthesis and preliminary biological evaluation of radiolabeled O6-benzylguanine derivatives, new potential PET imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in breast cancer
Zheng, Q., Liu, X., Fei, X., Wang, J.-Q., Ohannesian, D. W., Erickson, L. C., Stone, K. L., & Hutchins, G. D. (2003) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(02)00447-x · Cited by 35

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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