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Repair of O6-alkylguanine by alkyltransferases
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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“The MGMT, DUSP22, CDCA2, ID2, TNFRSF1B, ZNF681, and IGSF21 may have a role in the etiology and pathogenesis of this disease.[31][32][33][34][35][36][37][38][39][40]”
From Altered genome-wide methylation in endometriosis (2014) · cites this paper as [32]
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“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
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Genomic predictors of interindividual differences in response to DNA damaging agentsPreprint
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“MNNG induces a variety of alkylated DNA bases, among which O6-methylguanine (O6MeG) is known to be particularly toxic as well as mutagenic because it pairs with thymine during replication.”
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“TMZ generates a methylation at the O6 atom of guanine, O6-methylguanine lesions, resulting in DNA mismatch, and subsequent apoptosis (Pegg, 2000; Silber et al., 2012).”
BackgroundDNA-binding Mechanism ofO 6-Alkylguanine-DNA Alkyltransferase
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Metadata
- 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)
- 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
- 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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