| Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis. | |
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MedLine Citation:
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PMID: 20732909 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Methylating agents are widely distributed environmental carcinogens. Moreover, they are being used in cancer chemotherapy. The primary target of methylating agents is DNA, and therefore, DNA repair is the first-line barrier in defense against their toxic and carcinogenic effects. Methylating agents induce in the DNA O(6)-methylguanine (O(6)MeG) and methylations of the ring nitrogens of purines. The lesions are repaired by O(6)-methylguanine-DNA methyltransferase (Mgmt) and by enzymes of the base excision repair (BER) pathway, respectively. Whereas O(6)MeG is well established as a pre-carcinogenic lesion, little is known about the carcinogenic potency of base N-alkylation products such as N3-methyladenine and N3-methylguanine. To determine their role in cancer formation and the role of BER in cancer protection, we checked the response of mice with a targeted gene disruption of Mgmt or N-alkylpurine-DNA glycosylase (Aag) or both Mgmt and Aag, to azoxymethane (AOM)-induced colon carcinogenesis, using non-invasive mini-colonoscopy. We demonstrate that both Mgmt- and Aag-null mice show a higher colon cancer frequency than the wild-type. With a single low dose of AOM (3 mg/kg) Aag-null mice showed an even stronger tumor response than Mgmt-null mice. The data provide evidence that both BER initiated by Aag and O(6)MeG reversal by Mgmt are required for protection against alkylation-induced colon carcinogenesis. Further, the data indicate that non-repaired N-methylpurines are not only pre-toxic but also pre-carcinogenic DNA lesions. |
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Authors:
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Stefan Wirtz; Georg Nagel; Leonid Eshkind; Markus F Neurath; Leona D Samson; Bernd Kaina |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-23 |
Journal Detail:
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Title: Carcinogenesis Volume: 31 ISSN: 1460-2180 ISO Abbreviation: Carcinogenesis Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-01 Completed Date: 2011-01-06 Revised Date: 2011-06-06 |
Medline Journal Info:
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Nlm Unique ID: 8008055 Medline TA: Carcinogenesis Country: England |
Other Details:
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Languages: eng Pagination: 2111-7 Citation Subset: IM |
Affiliation:
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Department of Molecular Medicine, University of Erlangen-Nuremberg, D-91052 Erlangen, German. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Colonic Neoplasms / genetics, prevention & control* DNA Glycosylases / physiology DNA Repair* Female Male Methylation Mice Mice, Inbred C57BL O(6)-Methylguanine-DNA Methyltransferase / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA075576-14/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.21/DNA-3-methyladenine glycosidase II |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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