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Cell Growth & Differentiation Vol. 10, 749-758, November 1999
© 1999 American Association for Cancer Research


Articles

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

Mee Young Hong, Robert S. Chapkin, Christopher P. Wild, Jeffrey S. Morris, Naisyin Wang, Raymond J. Carroll, Nancy D. Turner and Joanne R. Lupton2

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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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.