title: Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis.
abstract: 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.
authors: Department of Molecular Medicine, University of Erlangen-Nuremberg, D-91052 Erlangen, German.
authors: Stefan
authors: S
authors: Wirtz
authors: Georg
authors: G
authors: Nagel
authors: Leonid
authors: L
authors: Eshkind
authors: Markus F
authors: MF
authors: Neurath
authors: Leona D
authors: LD
authors: Samson
authors: Bernd
authors: B
authors: Kaina
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000517:prevention & control*; D045647:DNA Glycosylases / Q000502:physiology; D004260:DNA Repair; D005260:Female; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000502:physiology*
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase; D045647:DNA Glycosylases; C076131:DNA-3-methyladenine glycosidase II