Repair and removal of azoxymethane-induced O^sup 6^-methylguanine in rat colon by O^sup 6^-methylguanine DNA methyltransferase and apoptosis

Azoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O...-methylguanine (O...meG) adducts in DNA. O...meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O...meG is important in developin...

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Bibliographic Details
Published in:Mutation research. Genetic toxicology and environmental mutagenesis 2013-12, Vol.758 (1-2), p.80
Main Authors: Nyskohus, Laura S, Watson, Amanda J, Margison, Geoffrey P, Le Leu, Richard K, Kim, Susan W, Lockett, Trevor J, Head, Richard J, Young, Graeme P, Hu, Ying
Format: Article
Language:English
Subjects:
Apoptosis
Colorectal cancer
Deoxyribonucleic acid
DNA
DNA methylation
Genomes
Proteins
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Summary:Azoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O...-methylguanine (O...meG) adducts in DNA. O...meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O...meG is important in developing preventive strategies for colorectal cancer. We explored the time-course, dose-response, and kinetics of O...meG formation and its removal by the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), and apoptosis. In rats given AOM (10 mg/kg), the formation of O...meG occurs within 2 h of exposure, accompanied by rapid depletion of MGMT activity and followed by the induction of an acute apoptotic response that peaks at 6-8 h. MGMT repair and apoptosis are dependent on AOM dose and O...meG load. Apoptosis is initiated only when a high O...meG load is present and MGMT activity is fully depleted. AOM, 10 mg/kg, overwhelms MGMT repair for about 96 h and renewed MGMT activity is only observed once O...meG is no longer detectable. A threshold for apoptosis is observed at 6 h after 6 mg/kg AOM, when a high O...meG persists and MGMT activity is very low. These data suggest that apoptosis is probably triggered by O...meG, but only once the capacity of MGMT to repair O...meG is exhausted. In the colonic epithelium, apoptosis may be complementary to MGMT, in terms of minimising potentially mutagenic events and maintaining a healthy genome. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:1383-5718
1879-3592