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

The DOI matches its Crossref record; 145 of the 167 references it cites were found in a registry or an index.

Repair of O6-alkylguanine by alkyltransferases

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1016/s1383-5742(00)00017-x

Cites

145 of 145 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia.
Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B., & Herman, J. G. (1999) · PubMed · Cited by 1,253
Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents.
Pegg, A. E. (1990) · PubMed · Cited by 734
Self-citation
REGULATION AND EXPRESSION OF THE ADAPTIVE RESPONSE TO ALKYLATING AGENTS
Lindahl, T. L., Sedgwick, B., Sekiguchi, M., & Nakabeppu, Y. (1988) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.57.070188.001025 · Cited by 650
Structure, Function, and Inhibition of O6-Alkylguanine-DNA Alkyltransferase
Pegg, A. E., Dolan, M. E., & Moschel, R. C. (1995) · Progress in nucleic acid research and molecular biology · doi:10.1016/s0079-6603(08)60879-x · Cited by 506
Self-citation
Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil‐DNA glycosylase with DNA
Parikh, S. S., Mol, C. D., Slupphaug, G., Bharati, S., Krokan, H. E., & Tainer, J. A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.5214 · Cited by 497
BASE FLIPPING
Roberts, R. J., & Cheng, X. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.181 · Cited by 315
Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.
Jaeckle, K. A., Eyre, H. J., Townsend, J. J., Schulman, S., Knudson, H. M., Belanich, M., Yarosh, D. B., Bearman, S., Giroux, D. J., & Schold, S. C. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.10.3310 · Cited by 297
Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis
D’Atri, S., Tentori, L., Lacal, P. M., Graziani, G., Pagani, E., Benincasa, E., Zambruno, G., Bonmassar, E., & Jiricny, J. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.2.334 · Cited by 282
Repair of DNA containing O 6 ‐alkylguanine
Pegg, A. E., & Byers, T. L. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.6.1544541 · Cited by 244
Self-citation
Ubiquitination-Dependent Proteolysis of O6-Methylguanine-DNA Methyltransferase in Human and Murine Tumor Cells following Inactivation with O6-Benzylguanine or 1,3-Bis(2-chloroethyl)-1-nitrosourea
Srivenugopal, K. S., Yuan, X., Friedman, H. S., & Ali‐Osman, F. (1996) · Biochemistry · doi:10.1021/bi9518205 · Cited by 218

Show all 167 references

Research works printed but not linked: 6

Kaur, 1999, Role of the O6-alkylguanine DNA alkyltransferase codons 143 and 160 polymorphisms in lung cancer risk, Proc. Am. Assoc. Cancer Res., 40, A1646
Egyhazi, 1999, Novel polymorphisms in the O6-methylguanine DNA methyltransferase gene in human melanoma, Proc. Am. Assoc. Cancer Res., 40, A3093
Crone, 1999, Ubiquitin-mediated proteolysis of O6-alkylguanine-DNA alkyltransferase following inactivation with O6-benzylguanine, Proc. Am. Assoc. Cancer Res., 40, A2656
Herfath, 1999, A specific CpG methylation pattern of the MGMT promoter region associated with reduced MGMT expression in primary colorectal cancers, Mol. Carcinog., 24, 90, 10.1002/(SICI)1098-2744(199902)24:2<90::AID-MC3>3.0.CO;2-B · DOI
Middleton, 1999, O6-(4-Bromothenyl)-guanine is an effective inactivator of O6-alkylguanine-DNA alkyltransferase, and improves the therapeutic index of temozolomide to a greater extent than O6-benzylguanine, Proc. Am. Assoc. Cancer Res., 40, A39
Friedman, 1999, The biology of sensitivity and resistance to the molecule (temozolomide), Proc. Am. Assoc. Cancer Res., 40, 754

Sorted by citations

Items 201–300 of 576

Chemotherapy resistance abrogation in metastatic melanoma.
Tawbi, H. A.-H., & Buch, S. C. (2010) · PubMed · Cited by 34
O 6 ‐alkylguanine‐DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer
Chae, M. H., Jang, J., Kang, H., Park, J. H., Park, J. M., Lee, W. K., Kam, S., Lee, E. B., Son, J. W., & Park, J. Y. (2005) · Molecular Carcinogenesis · doi:10.1002/mc.20171 · Cited by 34
“O(6)-alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein that removes mutagenic O(6)-alkylguanine (O(6)AG) DNA adducts that are formed by alkylating agents such as tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) [5,6].”
BackgroundInfluential
DNA repair in hybrid fish of the genus Xiphophorus
David, W. M., Mitchell, D. L., & Walter, R. B. (2004) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cca.2004.07.006 · Cited by 34
DNA Sequence Context Affects Repair of the Tobacco-Specific Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by Human O6-Alkylguanine-DNA Alkyltransferases
Mijal, R. S., Kanugula, S., Vu, C. C., Fang, Q., Pegg, A. E., & Peterson, L. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3803 · Cited by 34
“Nucleotide excision repair is thought to play a role in the repair of bulky O(6)-alkylguanine adducts (11).”
BackgroundSelf-citation
The Evolution of SNAP-Tag Labels
Dreyer, R., Pfukwa, R., Barth, S., Hunter, R., & Klumperman, B. (2023) · Biomacromolecules · doi:10.1021/acs.biomac.2c01238 · Cited by 33
Synthesis and characterization of an O6-2′-deoxyguanosine-alkyl-O6-2′-deoxyguanosine interstrand cross-link in a 5′-GNC motif and repair by human O6-alkylguanine-DNA alkyltransferase
McManus, F. P., Fang, Q., Booth, J. D. M., Noronha, A. M., Pegg, A. E., & Wilds, C. J. (2010) · Organic & Biomolecular Chemistry · doi:10.1039/c0ob00093k · Cited by 33
Self-citation
MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP
Jemth, A., Gustafsson, R., Bräutigam, L., Henriksson, L., Vallin, K. S. A., Sarno, A., Almlöf, I., Homan, E. J., Rasti, A., Berglund, U. W., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky896 · Cited by 30
Heterogeneity of Human Glioblastoma: Glutathione-S-Transferase and Methylguanine-Methyltransferase
Juillerat‐Jeanneret, L., Bernasconi, C. C., Bricod, C., Gros, S., Trepey, S., Benhattar, J., & Janzer, R. C. (2008) · Cancer Investigation · doi:10.1080/07357900802072913 · Cited by 35
Repair of O4-Alkylthymine by O6-Alkylguanine-DNA Alkyltransferases
Fang, Q., Kanugula, S., Tubbs, J. L., Tainer, J. A., & Pegg, A. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.045518 · Cited by 33
Self-citation
Novel synthesis of O6-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT)
Shibata, T. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl117 · Cited by 33
Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation ofO6-Alkylguanine-DNA Alkyltransferase byO6-Benzylguanine
Pauly, G. T., Loktionova, N. A., Fang, Q., Vankayala, S. L., Guida, W. C., & Pegg, A. E. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800675p · Cited by 32
Self-citation
Quantitative relationship between guanine O6-alkyl lesions produced by Onrigin™ and tumor resistance by O6-alkylguanine-DNA alkyltransferase
Ishiguro, K., Zhu, Y.-L., Shyam, K., Penketh, P. G., Baumann, R. P., & Sartorelli, A. C. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.022 · Cited by 32
“AGT is a unique DNA damage repair protein in that the transfer of an alkyl group to an AGT active site cysteine results in a stoichiometric irreversible inactivation of the protein [15,16].”
BackgroundInfluential
Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine
Ishiguro, K., Shyam, K., Penketh, P. G., & Sartorelli, A. C. (2005) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0169 · Cited by 32
“The O(6)-alkylguanine-specific repair protein AGT (12) was considered the most likely cause of the differential sensitivity.”
Background
Function of high-mobility group A proteins in the DNA damage signaling for the induction of apoptosis
Fujikane, R., Komori, K., Sekiguchi, M., & Hidaka, M. (2016) · Scientific Reports · doi:10.1038/srep31714 · Cited by 31
Replication Past the N5-Methyl-Formamidopyrimidine Lesion of Deoxyguanosine by DNA Polymerases and an Improved Procedure for Sequence Analysis of in Vitro Bypass Products by Mass Spectrometry
Christov, P. P., Angel, K. C., Guengerich, F. P., & Rizzo, C. J. (2009) · Chemical Research in Toxicology · doi:10.1021/tx900047c · Cited by 31
Interactions of Human O6-Alkylguanine-DNA Alkyltransferase (AGT) with Short Double-Stranded DNAs
Melikishvili, M., Rasimas, J. J., Pegg, A. E., & Fried, M. G. (2008) · Biochemistry · doi:10.1021/bi801666c · Cited by 31
Self-citation
Bifunctional DNA Alkylator 1,3-Bis(2-chloroethyl)-1-nitrosourea Activates the ATR-Chk1 Pathway Independently of the Mismatch Repair Pathway
Cui, B., Johnson, S. P., Bullock, N., Ali‐Osman, F., Bigner, D. D., & Friedman, H. S. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.053124 · Cited by 32
“These results demonstrate that the modulation of AGT by O6-BG potentiates Chk1 activation by BCNU, thus indicating that alkylation at the O6 position of guanine or the subsequently formed DNA interstrand cross-links are the primary BCNU-induced DNA lesions that trigger Chk1 activation.”
BackgroundInfluential
High incidence of MGMT promoter methylation in primary glioblastomas without correlation with TP53 gene mutations
Jesień-Lewandowicz, E., Jesionek‐Kupnicka, D., Zawlik, I., Szybka, M., Kulczycka-Wojdala, D., Rieske, P., Sieruta, M., Jaskólski, D. J., Och, W., Skowroński, W., et al. (2008) · Cancer Genetics and Cytogenetics · doi:10.1016/j.cancergencyto.2008.09.015 · Cited by 31
“Brain tumors expressing low levels of MGMT are more sensitive to chemotherapy based on alkylating agents, and MGMT depletion by Oebenzylguanine enhances the therapeutic efficacy in vitro and in patients [1,16,17].”
Background
Identification of WISP1 as a novel oncogene in glioblastoma
Jing, D., Zhang, Q., Yu, H., Zhao, Y., & Shen, L. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.4119 · Cited by 32
Intrinsic Anticancer Drug Resistance of Malignant Melanoma Cells Is Abrogated by IFN-β and Valproic Acid
Roos, W. P., Jöst, E., Belohlavek, C., Nagel, G., Fritz, G., & Kaina, B. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3498 · Cited by 30
DNA-Reactive Protein Monoepoxides Induce Cell Death and Mutagenesis in Mammalian Cells
Tretyakova, N. Y., Michaelson-Richie, E. D., Gherezghiher, T. B., Kurtz, J., Ming, X., Wickramaratne, S., Campion, M., Kanugula, S., Pegg, A. E., & Campbell, C. (2013) · Biochemistry · doi:10.1021/bi400273m · Cited by 30
Self-citation
p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis
MIAO, W., Liu, X., Wang, H., Fan, Y., Lian, S., Yang, X., Wang, X., GUO, G., LI, Q., & WANG, S. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3255 · Cited by 30
Prognostic significance of loss of O6-methylguanine-DNA methyltransferase expression in supratentorial diffuse low-grade astrocytoma
Nakasu, S., Fukami, T., Jito, J., & Matsuda, M. (2007) · Surgical Neurology · doi:10.1016/j.surneu.2006.12.053 · Cited by 30
“apeutic alkylating agents [10,28].”
S-phase Specific Downregulation of Human O6-Methylguanine DNA Methyltransferase (MGMT) and its Serendipitous Interactions with PCNA and p21cip1 Proteins in Glioma Cells
Mostofa, A., Punganuru, S. R., Madala, H. R., & Srivenugopal, K. S. (2018) · Neoplasia · doi:10.1016/j.neo.2018.01.010 · Cited by 30
Active‐site alkylation destabilizes human O6‐alkylguanine DNA alkyltransferase
Rasimas, J. J., Dalessio, P. A., Ropson, I. J., Pegg, A. E., & Fried, M. G. (2003) · Protein Science · doi:10.1110/ps.03319404 · Cited by 30
“However, it disappears rapidly from cells treated with DNA-alkylating agents or O6-benzylguanine (Pegg et al. 1995; Pegg 2000).”
BackgroundSelf-citation
Interaction of human and bacterial AlkB proteins with DNA as probed through chemical cross-linking studies
Mishina, Y. M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh319 · Cited by 30
Copper carbenes alkylate guanine chemoselectively through a substrate directed reaction
Geigle, S. N., Wyss, L. A., Sturla, S. J., & Gillingham, D. G. (2016) · Chemical Science · doi:10.1039/c6sc03502g · Cited by 29
Novel approaches for glioblastoma treatment: Focus on tumor heterogeneity, treatment resistance, and computational tools
Valdebenito, S., Damico, D. C. S., & Eugenín, E. A. (2019) · Cancer Reports · doi:10.1002/cnr2.1220 · Cited by 29
The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies
Maksoud, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02915-2 · Cited by 29
BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression
Tancredi, A., Gusyatiner, O., Bady, P., Buri, M. C., Lomazzi, R., Chiesi, D., Messerer, M., & Hegi, M. E. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05497-y · Cited by 29
Topologies of Complexes Containing O6-Alkylguanine–DNA Alkyltransferase and DNA
Adams, C., Melikishvili, M., Rodgers, D. W., Rasimas, J. J., Pegg, A. E., & Fried, M. G. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.03.067 · Cited by 29
Self-citation
Structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein
Perugino, G., Miggiano, R., Serpe, M., Vettone, A., Valenti, A., Lahiri, S., Rossi, F., Rossi, M., Rizzi, M., & Ciaramella, M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv774 · Cited by 30
An Update on the Epigenetics of Glioblastomas
Ferreira, W. A. S., Pinheiro, D. D. R., da Costa, C. A., Rodrigues-Antunes, S., Araújo, M. D., Barros, M. B. L., Teixeira, A. C. D. S., Faro, T. A. S., Burbano, R. M. R., de Oliveira, E. H. C., et al. (2016) · Epigenomics · doi:10.2217/epi-2016-0040 · Cited by 29
Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis
An, N., Shi, Y., Ye, P., Pan, Z., & Long, X. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000480196 · Cited by 29
Genotoxic effects of myosmine in a human esophageal adenocarcinoma cell line
Vogt, S., Fuchs, K., & Richter, E. (2006) · Toxicology · doi:10.1016/j.tox.2006.01.025 · Cited by 29
Fluorescent reporter assays provide direct, accurate, quantitative measurements of MGMT status in human cells
Nagel, Z. D., Beharry, A. A., Mazzucato, P., Kitange, G. J., Sarkaria, J. N., Kool, E. T., & Samson, L. D. (2019) · PLoS ONE · doi:10.1371/journal.pone.0208341 · Cited by 28
Analysis of O6-methylguanine-DNA methyltransferase in melanoma tumours in patients treated with dacarbazine-based chemotherapy
Ma, S., Egyházi, S., Martenhed, G., Ringborg, U. K., & Hansson, J. (2002) · Melanoma Research · doi:10.1097/00008390-200208000-00005 · Cited by 28
Fluorogenic Real-Time Reporters of DNA Repair by MGMT, a Clinical Predictor of Antitumor Drug Response
Beharry, A. A., Nagel, Z. D., Samson, L. D., & Kool, E. T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152684 · Cited by 28
“However, fluorophore-labeled BG (or SNAP-tag probes) are poor substrates for wild-type MGMT [19,39] and as a consequence the fluorescence response with enzyme was slow, requiring high concentrations of probe (5 μM) to produce signals on a timescale of hours.”
Background
Promoter methylation of O6-methylguanine-DNA-methyltransferase in lung cancer is regulated by p53
Lai, J.-C., Cheng, Y., Goan, Y.-G., Chang, J. T., Wu, T., Chen, C., & Lee, H. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.04.016 · Cited by 28
Molecular Dosimetry of Temozolomide: Quantification of Critical Lesions, Correlation to Cell Death Responses, and Threshold Doses
Stratenwerth, B., Geisen, S. M., He, Y., Beltzig, L., Sturla, S. J., & Kaina, B. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0228 · Cited by 29
Protein expression and methylation of DNA repair genes hMLH1, hMSH2, MGMT and BRCA1 and their correlation with clinicopathological parameters and prognosis in basal‐like breast cancer
Yimit, A., Mitomi, H., Nakai, K., Himuro, T., Saito, T., Takahashi, M., Arakawa, A., Yao, T., & Saito, M. (2013) · Histopathology · doi:10.1111/his.12220 · Cited by 27
Thresholds for DNA-Reactive (Genotoxic) Organic Carcinogens
Williams, G. M., Iatropoulos, M. J., & Jeffrey, A. M. (2005) · Journal of Toxicologic Pathology · doi:10.1293/tox.18.69 · Cited by 27
A novel DNA damage recognition protein in Schizosaccharomyces pombe
Pearson, S. J. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl270 · Cited by 27
“The alkyl acceptor cysteine is part of the motif PCHRI/V that is found in all functional alkyltransferase proteins and substitution of this residue inactivates the protein ( 7 ).”
Background
O6-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C
Passagne, I., Evrard, A., Depeille, P., Cuq, P., Cupissol, D., & Vian, L. (2005) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2005.06.009 · Cited by 27
Novel DNA repair alkyltransferase from Caenorhabditis elegans
Kanugula, S., & Pegg, A. E. (2001) · Environmental and Molecular Mutagenesis · doi:10.1002/em.1077 · Cited by 27
“Many organisms have developed an effective mechanism to repair these mutagenic lesions through the action of O6-alkylguanine DNA-alkyltransferase (AGT) (EC 2.1.1.63) [Lindahl et al., 1988; Moore et al., 1994; Pegg et al., 1995; Pegg, 2000].”
BackgroundInfluentialSelf-citation
Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O6-Methylguanine DNA-Methyltransferase Expression
Passagne, I., Evrard, A., Winum, J., Depeille, P., Cuq, P., Montero, J., Cupissol, D., & Vian, L. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.051938 · Cited by 27
Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy
Raizer, J. J., Malkin, M. G., Kleber, M., & Abrey, L. E. (2004) · Neuro-Oncology · doi:10.1215/s1152851704000122 · Cited by 27
“Additionally, blockade or depletion of AGT may enhance the cytotoxicity of nitrosoureas and alkylating agents (Gerson, 2002; Pegg, 2000; Wedge et al., 1996).”
BackgroundInfluential
Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection
Milsom, M. D., & Williams, D. A. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.03.020 · Cited by 26
The nitrosated bile acid DNA lesion O6 -carboxymethylguanine is a substrate for the human DNA repair protein O6 -methylguanine-DNA methyltransferase
Senthong, P., Millington, C. L., Wilkinson, O. J., Marriott, A. S., Watson, A. J., Reamtong, O., Eyers, C. E., Williams, D. M., Margison, G. P., & Povey, A. C. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks1476 · Cited by 26
Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth
Ramirez, Y. P., Mladek, A. C., Phillips, R. M., Gynther, M., Rautio, J., Ross, A. H., Wheelhouse, R. T., & Sakaria, J. N. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0113 · Cited by 27
Oxidative Stress in DNA Damage and Neurodegenerative Diseases: Unveiling The Mechanisms and Therapeutic Opportunities
Rahman, M. A., Khatun, M. T., Mim, A. K., Khandocar, M. P., Rahman, A., Hasan, M. H., Shimki, A. I., Hossain, M. S., Shoily, M. S. A., Faraque, A., et al. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01845-9 · Cited by 27
“Understanding mutations and polymorphisms in critical DNA repair genes should pave the way for more effective treatments for degenerative disorders [208 – 210].”
DNA Repair Mechanisms and Therapeutic Targets in Glioma
Elmore, K. B., & Schaff, L. R. (2021) · Current Oncology Reports · doi:10.1007/s11912-021-01077-z · Cited by 24
Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis
Lee, K.-H., Kim, S., Kim, E. E., Shim, Y., Won, J., Park, C., Choi, S. H., Yun, H., Lee, H., & Park, S. (2023) · Scientific Reports · doi:10.1038/s41598-023-32153-y · Cited by 25
MGMT Ile143Val polymorphism, dietary factors and the risk of breast, colorectal and prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study
Loh, Y. H., Mitrou, P. N., Bowman, R., Wood, A., Jeffery, H., Luben, R., Lentjes, M. A. H., Khaw, K., & Rodwell, S. A. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.01.002 · Cited by 25
Cigarette Smoke-Induced Failure of Apoptosis Resulting in Enhanced Neoplastic Transformation in Human Bronchial Epithelial Cells
Du, H.-B., Sun, J., Chen, Z., Nie, J., Tong, J., & Li, J. (2012) · Journal of Toxicology and Environmental Health · doi:10.1080/15287394.2012.690088 · Cited by 25
“MGMT protein is a DNA repair enzyme involved in the transfer of methyl groups and other small alkyl groups at the O 6 position of guanine to a cysteine acceptor site of the protein in an auto-inactivating reaction ( Pegg 2000 ).”
Background
A genotoxic screen: rapid analysis of cellular dose–response to a wide range of agents that either damage DNA or alter genome maintenance pathways
Marple, T. C., Li, H., & Hasty, P. (2004) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2004.05.004 · Cited by 25
Chemotherapy-induced O(6)-benzylguanine-resistant alkyltransferase mutations in mismatch-deficient colon cancer.
Liu, L., Schwartz, S., Davis, B. M., & Gerson, S. L. (2002) · PubMed · Cited by 25
A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM]
Gibson, D. R., Vo, A. H., Lambing, H., Bhattacharya, P., Tahir, P., Chehab, F. F., & Butowski, N. A. (2024) · BMC Neurology · doi:10.1186/s12883-024-03605-3 · Cited by 24
Prognostic significance of O6‐methylguanine DNA methyltransferase and p57 methylation in patients with diffuse large B‐cell lymphomas
Lee, S., Lee, E. J., Ko, Y. H., Lee, S. H., Maeng, L.-S., & Kim, K. (2009) · Apmis · doi:10.1111/j.1600-0463.2008.00017.x · Cited by 23
Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals
Hansen, R. J., Ludeman, S. M., Paikoff, S. J., Pegg, A. E., & Dolan, M. E. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.03.010 · Cited by 24
“MGMT activity is restored in the cell after de novo synthesis [7,8].”
BackgroundSelf-citation
Alkyltransferase-like proteins: molecular switches between DNA repair pathways
Tubbs, J. L., & Tainer, J. A. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0405-8 · Cited by 24
“DNA O(6)-alkylguanine (O(6)-alkylG) lesions are mostly repaired through the action of alkyltransferase proteins, such as Ada and Ogt in Escherichia coli, and O(6)-alkylguanine-DNA alkyltransferase (AGT) (also known as O(6)-methylguanine-DNA methyltransferase, MGMT, in humans), which are widespread amongst prokaryotes…”
Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6‐alkylguanine–DNA alkyltransferase
Crosbie, P. A. J., McGown, G., Thorncroft, M. R., O’Donnell, E., Barber, P. V., Lewis, S. J., Harrison, K., Agius, R. M., Santibanez‐Koref, M., Margison, G. P., et al. (2007) · International Journal of Cancer · doi:10.1002/ijc.23059 · Cited by 24
Association between small heat shock protein B11 and the prognostic value of MGMT promoter methylation in patients with high-grade glioma
Cheng, W., Li, M., Jiang, Y., Zhang, C., Cai, J., Wang, K., & Wu, A. (2015) · Journal of neurosurgery · doi:10.3171/2015.5.jns142437 · Cited by 24
Comparative proteogenomic characterization of glioblastoma
Asif, S., Fatima, R., Krc, R., Bennett, J., & Raza, S. (2019) · CNS Oncology · doi:10.2217/cns-2019-0003 · Cited by 25
Promoter Hypermethylation of the DNA-Repair Gene O 6 -Methylguanine-DNA Methyltransferase and p53 Mutation in Diffuse Large B-Cell Lymphoma
Hiraga, J., Kinoshita, T., Ohno, T., Mori, N., Ohashi, H., Fukami, S., Noda, A., Ichikawa, A., & Naoe, T. (2006) · International Journal of Hematology · doi:10.1532/ijh97.06087 · Cited by 24
Amino acid substitution polymorphisms of the DNA repair gene MGMT and the susceptibility to cervical carcinoma
Huang, J., Ye, F., Chen, H., Lu, W., & Xie, X. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm003 · Cited by 24
“Methyltransferase activity between human fibroblast cultures from different individuals varies as much as 20-fold, suggesting that genetic polymorphisms in MGMT are risk factors for the development of cancer [34-36].”
Background
Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents
Lees, N. P. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh111 · Cited by 24
“O6-Methylguanine levels will however depend not only on exposure but also upon the level of O6-alkylguanine DNA-alkyltransferase (MGMT), which repairs O6-methylguanine and becomes inactivated in the process ( 4 ,5).”
BackgroundMethodInfluential
Determination of the optimal modulatory dose of O6-benzylguanine in patients with surgically resectable tumors.
Dolan, M. E., Posner, M. C., Karrison, T. G., Radosta, J. M., Steinberg, G. D., BERTUCCI, D. C., Vujasin, L., & Ratain, M. J. (2002) · PubMed · Cited by 24
Crystal structure of Mycobacterium tuberculosis O6-methylguanine-DNA methyltransferase protein clusters assembled on to damaged DNA
Miggiano, R., Perugino, G., Ciaramella, M., Serpe, M., Rejman, D., Páv, O., Pohl, R., Garavaglia, S., Lahiri, S., Rizzi, M., et al. (2015) · Biochemical Journal · doi:10.1042/bj20150833 · Cited by 23
Correlation between promoter hypermethylation of GSTP1 and response to chemotherapy in diffuse large B cell lymphoma
Nakamichi, I., Tomita, Y., Zhang, B., Sugiyama, H., Kanakura, Y., Fukuhara, S., Hino, M., Kanamaru, A., Ogawa, H., & Aozasa, K. (2007) · Annals of Hematology · doi:10.1007/s00277-007-0299-1 · Cited by 24
“activity is supposed to play a major role in resistance to alkylating agents [ 21 ].”
Background
Alkyltransferase-Mediated Toxicity of 1,3-Butadiene Diepoxide
Kalapila, A. G., Loktionova, N. A., & Pegg, A. E. (2008) · Chemical Research in Toxicology · doi:10.1021/tx800178t · Cited by 23
Self-citation
Mutagenicity associated with O6-methylguanine-DNA damage and mechanism of nucleotide flipping by AGT during repair
Jena, N. R., & Bansal, M. (2011) · Physical Biology · doi:10.1088/1478-3975/8/4/046007 · Cited by 23
Lung cancer risk and variation in MGMT activity and sequence
Povey, A. C., Margison, G. P., & Santibanez‐Koref, M. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.03.022 · Cited by 23
Cloudy apple juice protects against chemical-induced oxidative stress in rat
Kujawska, M., Ignatowicz, E., Ewertowska, M., Markowski, J., & Jodynis‐Liebert, J. (2010) · European Journal of Nutrition · doi:10.1007/s00394-010-0114-y · Cited by 23
“High doses of alkylating agents caused a depletion of this repair mechanism [ 34 ].”
Background
Prognostic significance of epigenetic inactivation of p16, p15, MGMT and DAPK genes in follicular lymphoma
Krajnović, M., Radojković, M., Davidović, R. S., Dimitrijević, B., & Krtolica, K. (2012) · Medical Oncology · doi:10.1007/s12032-012-0441-3 · Cited by 22
New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy
Ameya, P., Nathan, I., Konduri, S. D., George, C., Francis, A.-O., Mohd, A., Surendra, R., Madala, H. R., Basak, D., Mostofa, A. G. M., et al. (2016) · Journal of Biomedical Research · doi:10.7555/jbr.30.20160040 · Cited by 22
Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research
Jiang, G., Jiang, A., Xin, Y., Li, L., Qian, C., & Zheng, J. (2014) · Molecular Biology Reports · doi:10.1007/s11033-014-3549-z · Cited by 22
Inactivation of O6-Alkylguanine-DNA Alkyltransferase by Folate Esters of O6-Benzyl-2‘-deoxyguanosine and of O6-[4-(Hydroxymethyl)benzyl]guanine
Javanmard, S., Loktionova, N. A., Fang, Q., Pauly, G. T., Pegg, A. E., & Moschel, R. C. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm0705859 · Cited by 22
“O6-Benzyl-3′-O-(γ-folyl)-2′-deoxyguanosine (1)”
BackgroundSelf-citation
Structural studies of MJ1529, an O6-methylguanine-DNA methyltransferase
Roberts, A., Pelton, J. G., & Wemmer, D. E. (2006) · Magnetic Resonance in Chemistry · doi:10.1002/mrc.1823 · Cited by 22
Human colorectal mucosal O 6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents
Lees, N. P., Harrison, K., Hall, C. N., Margison, G. P., & Povey, A. C. (2006) · Gut · doi:10.1136/gut.2006.097899 · Cited by 22
The best of both worlds: Chemigenetic fluorescent sensors for biological imaging
Tsao, K., Imai, S., Chang, M., Hario, S., Terai, T., & Campbell, R. E. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.08.002 · Cited by 21
Novel Imidazotetrazine Evades Known Resistance Mechanisms and Is Effective against Temozolomide-Resistant Brain Cancer in Cell Culture
Svec, R. L., McKee, S. A., Berry, M. R., Kelly, A. M., Fan, T. M., & Hergenrother, P. J. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.2c00022 · Cited by 24
Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect
Gibson, D., Ravi, A., Rodriguez, E., Chang, S. M., Bush, N. A. O., Taylor, J. W., Clarke, J. L., Solomon, D. A., Scheffler, A., Witte, J. S., et al. (2023) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdad115 · Cited by 21
“4,5,9,10 Furthermore, AGT does not associate or work in concert with other transcription-coupled repair proteins, indicating AGT ’s in-dependence as a repair mechanism.”
Background
Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of temozolomide
Matsuno, A., Murakami, M., Hoya, K., Yamada, S. M., Miyamoto, S., Yamada, S., Son, J.-H., Nishido, H., Ide, F., Nagashima, H., et al. (2013) · Medical Molecular Morphology · doi:10.1007/s00795-013-0050-z · Cited by 21
“Among many mechanisms of resistance to alkylating agents, the expression of MGMT has a protective effect against cell death induced by alkylating agents, showing a strong correlation between MGMT activity and drug resistance [43, 44].”
Background
Protective effect of chokeberry on chemical-induced oxidative stress in rat
Kujawska, M., Ignatowicz, E., Ewertowska, M., Oszmiański, J., & Jodynis‐Liebert, J. (2010) · Human & Experimental Toxicology · doi:10.1177/0960327110371697 · Cited by 21
Differential effects of low- and high-dose X-rays on N-ethyl-N-nitrosourea-induced mutagenesis in thymocytes of B6C3F1 gpt-delta mice
Yamauchi, K., Kakinuma, S., 須藤, 聡., Kito, S., Ohta, Y., Nohmi, T., Masumura, K., Nishimura, M., & Shimada, Y. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2007.12.001 · Cited by 21
Escherichia coli BTC, a human cytochrome P450 competent tester strain with a high sensitivity towards alkylating agents: involvement of alkyltransferases in the repair of DNA damage induced by aromatic amines
Duarte, M. P., Palma, B. B., Laires, A., Oliveira, J. S., Rueff, J., & Kranendonk, M. (2005) · Mutagenesis · doi:10.1093/mutage/gei028 · Cited by 21
Endoplasmic reticulum protein 29 (ERp29) confers radioresistance through the DNA repair gene, O6-methylguanine DNA-methyltransferase, in breast cancer cells
Chen, S., Zhang, Y., & Zhang, D. (2015) · Scientific Reports · doi:10.1038/srep14723 · Cited by 21
Mécanismes de réparation et mutagenèse radio-induite chez les eucaryotes supérieurs
Averbeck, D. (2000) · Cancer/Radiothérapie · doi:10.1016/s1278-3218(00)00008-1 · Cited by 20
The delayed genotoxic effect of N-nitroso N-propoxur insecticide in mammalian cells
Lin, C., Wei, L., & Wang, T.-C. (2006) · Food and Chemical Toxicology · doi:10.1016/j.fct.2006.11.015 · Cited by 20
Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents
Xu, M., Nekhayeva, I., Cross, C. E., Rondelli, C. M., Wickliffe, J. K., & Abdel-Rahman, S. Z. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt355 · Cited by 20
Kinetics of O6-Methyl-2‘-deoxyguanosine Repair by O6-Alkylguanine DNA Alkyltransferase within K-ras Gene-Derived DNA Sequences
Guza, R., Rajesh, M. P., Fang, Q., Pegg, A. E., & Tretyakova, N. Y. (2006) · Chemical Research in Toxicology · doi:10.1021/tx050348d · Cited by 20
Self-citation
The SNAP- tag technology revised: an effective chemo-enzymatic approach by using a universal azide-based substrate
Merlo, R., Caprioglio, D., Cillo, M., Valenti, A., Mattossovich, R., Morrone, C., Massarotti, A., Rossi, F., Miggiano, R., Leonardi, A., et al. (2020) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2020.1841182 · Cited by 19
Evaluation of Methylation of MGMT ( O 6 -Methylguanine-DNA Methyltransferase) Gene Promoter in Sporadic Colorectal Cancer
Farzanehfar, M., Vossoughinia, H., Jabini, R., Tavassoli, A., Saadatnia, H., Khorashad, A. K., Ahadi, M., Afzalaghaee, M., Karimiani, E. G., Mirzaei, F., et al. (2013) · DNA and Cell Biology · doi:10.1089/dna.2012.1949 · Cited by 18
“The DNA repair protein encoded by the O 6 -methylguanine-DNA methyltransferase (MGMT) gene is involved in defending cells against alkylating agents (Pegg, 2000; Kaina et al. , 2001).”
Degradation of BRCA2 in Alkyltransferase-Mediated DNA Repair and Its Clinical Implications
Philip, S., Swaminathan, S., Kuznetsov, S. G., Kanugula, S., Biswas, K., Chang, S., Loktionova, N. A., Haines, D. C., Kaldis, P., Pegg, A. E., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1179 · Cited by 20
“AGT functions by transferring the alkyl group from the O 6 position of guanine in DNA to a cysteine residue within its active site ( 20 ).”
Self-citation
Repair of O6-methylguanine adducts in human telomeric G-quadruplex DNA by O6-alkylguanine-DNA alkyltransferase
Hellman, L. M., Spear, T. J., Koontz, C. J., Melikishvili, M., & Fried, M. G. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku659 · Cited by 19
Novel role of triazenes in haematological malignancies: Pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia
Caporaso, P., Turriziani, M., Venditti, A., Marchesi, F., Buccisano, F., Tirindelli, M. C., Alvino, E., Garbin, A., Tortorelli, G., Toppo, L., et al. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.03.016 · Cited by 19
Interdomain interactions rearrangements control the reaction steps of a thermostable DNA alkyltransferase
Morrone, C., Miggiano, R., Serpe, M., Massarotti, A., Valenti, A., del Monaco, G., Rossi, M., Rossi, F., Rizzi, M., Perugino, G., et al. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.10.020 · Cited by 19
Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine
Frederick, A. M., Davis, M. L., & Rice, K. P. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.042 · Cited by 19
6-Carboxyfluorescein and structurally similar molecules inhibit DNA binding and repair by O6-alkylguanine DNA alkyltransferase
Melikishvili, M., Rodgers, D. W., & Fried, M. G. (2011) · DNA repair · doi:10.1016/j.dnarep.2011.09.007 · Cited by 19
“Is FAM a prototype drug? The DNA-alkyltransferase activity of AGT protects tumor cells from toxic effects of DNA-alkylating chemotherapeutic drugs [8,44,59].”
Background

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Repair of O6-alkylguanine by alkyltransferases

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks