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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Rozov, F. N., Grinenko, T., Левит, Г. Л., Grishakov, A. N., Belyavsky, A. V., & Krasnov, V. P. (2011) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162011060112 · Cited by 3
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“O6-alkylguanine-DNA alkyltransferases (AGTs), which are found in all kingdoms of life except plants, play an important role in maintaining the genomic code due to their ability to repair both O6-alkyl guanine and O4-alkyl thymine damage [3].”
Background
Transcriptional Pausing and Activation at Exons-1 and -2, Respectively, Mediate the MGMT Gene Expression in Human Glioblastoma Cells
Al-Obaide, M. A. I., & Srivenugopal, K. S. (2021) · Genes · doi:10.3390/genes12060888 · Cited by 3
“Introduction O6-Methylguanine-DNA-methyltransferase (MGMT) is a simple, low molecular weight (~23 kDa), antimutagenic DNA repair protein expressed in varying amounts in normal tissues, but generally, at elevated levels in human malignancies including brain cancers [1,2].”
Background
Species-specific mobile genetic elements in the gene of repair enzyme MGMT in new world monkeys
Пидпала, О. В., & Лукаш, Л. Л. (2021) · Faktori eksperimental noi evolucii organizmiv · doi:10.7124/feeo.v28.1388 · Cited by 3
Carcinogenic Effects of Cigarette Smoke on the Respiratory Tract*
Peterson, L. A., Urban, A. M., & Hecht, S. S. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-046884-6.00919-2 · Cited by 3
I. DNA-protein cross-linking by CIS-1,1,2,2-diamminedichloroplatinum (II) (cisplatin) II. formation of 8-OXO-dG and oxazolone lesions with p53 II. derived DNA sequences following photooxidation in the presence of riboflavin
Ming, X. (2011) · University of Minnesota Digital Conservancy (University of Minnesota) · Cited by 3
AGT/SNAP‐Tag: A Versatile Tag for Covalent Protein Labeling
Gautier, A., Johnsson, K., & O’Hare, H. M. (2008) · doi:10.1002/9783527623099.ch5 · Cited by 3
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Franceschi, E., Tosoni, A., & Brandes, A. A. (2008) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.8.5.663 · Cited by 3
O6-3-[125I]iodobenzyl-2′-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT)
Shankar, S., Zalutsky, M. R., & Vaidyanathan, G. (2005) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2005.04.014 · Cited by 3
SNAPpa: A Photoactivatable SNAP-tag for the Spatiotemporal Control of Protein Labeling
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E3 ligase LMO7 enhances temozolomide sensitivity by promoting MGMT degradation in lung cancer
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“Higher MGMT protein expression has been associated with TMZ resistance in glioblastoma, where TMZ is used as a first-line therapy, and similar associations have been reported in NSCLC (23–28).”
The expression of O6-methylguanine-DNA methyltransferase in the spontaneously immortalized mouse cell line G1 and its sublines G1-OA and G1-T
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Gulati, I., Patel, H., Prabhakar, B. R., & Nair, S. (2020) · Current pharmacogenomics and personalized medicine (Online)/Current pharmacogenomics and personalized medicine · doi:10.2174/1875692118666200309130307 · Cited by 2
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Zhuvaka, K. S., Volynets, G. P., Ruban, T. P., Nidoeva, Z. M., Iatsyshyna, A. P., Macewizc, L. L., Bdzhola, V. G., Yarmoluk, S. M., & Лукаш, Л. Л. (2023) · Cytology and Genetics · doi:10.3103/s0095452723060105 · Cited by 2
“Those inhibitors have a high affinity to the enzyme and function as so-called MGMT pseudosubstrates (Pegg, 2000; Mitra, 2007).”
Background
Role of Non-coding RNAs in the Response of Glioblastoma to Temozolomide
Goleij, P., Pourali, G., Raisi, A., Ravaei, F., Golestan, S., Abed, A., Razavi, Z. S., Zarepour, F., Taghavi, S. P., Asouri, S. A., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04316-z · Cited by 2
“A subtype of O6-alkylguanine DNA alkyl transferase (AGT), O6-methylguanine DNA methyl transferase (MGMT) is crucial for defending human DNA from alkylating chemicals’ damage to nucleic acids [88, 89].”
Explainable Machine-Learning for identifying the genetic biomarker MGMT in brain tumors using magnetic resonance imaging radiomics
Ponce, S., Chabert, S., Mayeta-Revilla, L., Franco, P., Plaza, F., Querales, M., & Rodrigo Salas, F. (2024) · International Conference on Pattern Recognition Systems (ICPRS) · doi:10.1109/icprs62101.2024.10677829 · Cited by 2
“This gene, located on chromosomal band 10q26, encodes a DNA repair enzyme crucial in preventing carcinogenesis and resistance to chemotherapy with alkylating agents [4].”
Background
Overcoming Resistance to Alkylating Agents by Inhibitors of O 6-Alkylguanine-DNA Alkyltransferase
Pegg, A. E., & Dolan, M. E. (2004) · doi:10.1007/978-1-59259-735-2_7 · Cited by 2
Self-citation
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Kokunai, Y., Tsuji, M., Ito, Y., KUROKAWA, T., Otsuki, Y., & Moriwaki, S. (2013) · Medical Molecular Morphology · doi:10.1007/s00795-013-0030-3 · Cited by 2
Chapter 5 Molecular Mechanisms of 4‐(Methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone‐Induced Lung Carcinogenesis
Peterson, L. A. (2009) · Advances in molecular toxicology · doi:10.1016/s1872-0854(09)00005-8 · Cited by 2
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Gatti, A., di Meo, N., Stinco, G., Malagoli, M., Bonin, S., & Trevisan, G. (2014) · Journal of Cutaneous Medicine and Surgery · doi:10.2310/7750.2013.13045 · Cited by 2
“An important mechanism of resistance to methylating agents is deoxyribonucleic acid (DNA) repair mediated by the enzyme O6-alkylguanineDNA alkyltransferase protein (O6-methylguanine-DNA methyltransferase [MGMT]).2 It removes drug-induced alkylguanine adducts from DNA.3 High levels of MGMT activity in cancer cells crea…”
Background
In silico analysis of MGMT gene orthologous in the most ancient mammals Strepsirrhini
Пидпала, О. В., & Лукаш, Л. Л. (2020) · Faktori eksperimental noi evolucii organizmiv · doi:10.7124/feeo.v26.1284 · Cited by 2
MGMT
Liu, L., Lin, Y., & Gerson, S. L. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-384999-1.10002-2 · Cited by 2
Protein Conjugates of SH3‐Domain Ligands and ATP‐Competitive Inhibitors as Bivalent Inhibitors of Protein Kinases
Tiwari, R. K., & Parang, K. (2009) · ChemBioChem · doi:10.1002/cbic.200900462 · Cited by 2
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Klapacz, J., & Gollapudi, B. B. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.95611-3 · Cited by 2
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Sidorenko, Y. S., Kit, O. I., Popov, I. A., Shikhlyarova, A. I., Rostorguev, E. E., Тимошкина, Н. Н., Gusareva, M. A., Arapova, Y. Y., Potemkin, D. S., Pushkin, A. A., et al. (2020) · Siberian Journal of Oncology · doi:10.21294/1814-4861-2019-18-6-57-66 · Cited by 2
Multidrug resistance in solid tumours
Nicolantonio, F. D. (2004) · OpenGrey (Institut de l'Information Scientifique et Technique) · Cited by 2
Fluorescence Labeling
Nienhaus, G. U., & Nienhaus, K. (2013) · doi:10.1002/9783527671595.ch4 · Cited by 2
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Kycler, W., Korski, K., Łoziński, C., Teresiak, A., Przybyła, A., Mackiewicz, A. A., Cybulski, Z., & Lamperska, K. M. (2014) · Pharmacological Reports · doi:10.1016/j.pharep.2014.06.019 · Cited by 1
Human O6‐methylguanine‐DNA methyltransferase containing C145A does not prevent hepatocellular carcinoma in C3HeB/FeJ transgenic mice
Herzig, M. C. S., Hildreth, K., Huamani, J., Perez, M., Goins, B., McMahan, C. A., Reddick, R. L., & Walter, C. A. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.21855 · Cited by 1
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Skórski, T. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-199-4_12 · Cited by 1
“Direct reversion Methylguanine-DNA methyltransferase (MGMT) transfers the methyl group from the DNA to an internal cysteine residue on the MGMT protein ( 40 ).”
Background
DNA direct repair pathways in cancer
Gutierrez, R., Thompson, Y., & O'Connor, T. R. (2018) · AIMS Medical Science · doi:10.3934/medsci.2018.3.284 · Cited by 2
NUCLEOTIDE EXCISION REPAIR (NER)
Lehmann, A. (2013) · CRC Press eBooks · doi:10.1201/b14587-6 · Cited by 1
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Juarez, T., Gill, J. M., Minev, B., Sharma, A., & Kesari, S. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104596 · Cited by 1
Topological Probes of a Cooperative, Nonspecific Protein–DNA Complex
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Guanine 6‐O‐Methylation Pattern within the Dioxin Responsive Element of the CYP1A1 Enhancer Shows Two Critical Guanines for AhR/ARNT Binding
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Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of O6-methylguanine and their recognition by MGMT and Atl1
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“Insertion of thymine opposite O(6)-alkGs during DNA replication can result in GC->AT transition mutations, that are a common feature of many tumours([1]) and In humans the protein O(6)-methylguanine-DNA-methyltransferase (MGMT) repairs O(6)-methylguanine [O(6)-MeG (1)] and other O(6)-alkGs via the irreversible transfe…”
Background
Glioblastoma: State of the Art of Treatments and Applications of Polymeric and Lipidic Nanomedicines
Sgarbi, V., Duskey, J. T., Ottonelli, I., Ros, F. D., Oddone, N., Vandelli, M. A., Forni, F., Tosi, G., & Ruozi, B. (2020) · Neuromethods · doi:10.1007/978-1-0716-1052-7_1 · Cited by 1
Computational Approaches for Structure Based Drug Design and Protein Structure-Function Prediction
Vankayala, S. L. (2013) · Digital Commons - University of South Florida (University of South Florida) · Cited by 1
DNA Repair in Resistance to Bifunctional Alkylating and Platinating Agents
Murray, D. L. (2002) · Cancer treatment and research · doi:10.1007/978-1-4615-1173-1_7 · Cited by 1
Tyrosinemia type I as a model for studying epigenetic events in the aetiology of metabolic disease associated hepatocarcinoma
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Effect of sequence context on the formation and repair of DNA adducts.
Guza, R. (2009) · University of Minnesota Digital Conservancy (University of Minnesota) · Cited by 1

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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