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Relationship between DNA Adduct Levels, Repair Enzyme, and Apoptosis as a Function of DNA Methylation by Azoxymethane¹

Faculty of Nutrition [M. Y. H., R. S. C., R. J. C., N. D. T., J. R. L.], and the Department of Statistics [J. S. M., N. W., R. J. C.], Texas A &M University, College Station, Texas 77843-2471, and Molecular Epidemiology Unit, School of Medicine, University of Leeds, Leeds, LS2 9JT United Kingdom [C. P. W.]

Abstract

DNA alkylating agent exposure results in the formation of a number of DNA adducts, with O⁶-methyl-deoxyguanosine (O⁶-medG) being the major mutagenic and cytotoxic DNA lesion. Critical to the prevention of colon cancer is the removal of O⁶-medG DNA adducts, either through repair, for example, by O⁶-alkylguanine-DNA alkyltransferase (ATase) or targeted apoptosis. We report how rat colonocytes respond to administration of azoxymethane (a well-characterized experimental colon carcinogen and DNA-methylating agent) in terms of O⁶-medG DNA adduct formation and adduct removal by ATase and apoptosis. Our results are: (a) DNA damage is greater in actively proliferating cells than in the differentiated cell compartment; (b) expression of the DNA repair enzyme ATase was not targeted to the proliferating cells or stem cells but rather is confined primarily to the upper portion of the crypt; (c) apoptosis is primarily targeted to the stem cell and proliferative compartments; and (d) the increase in DNA repair enzyme expression over time in the bottom one-third of the crypt corresponds with the decrease in apoptosis in this same crypt region.

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