Relationship between DNA adduct levels, repair enzyme, and apoptosis as a function of DNA methylation by azoxymethane

DNA alkylating agent exposure results in the formation of a number of DNA a dducts, with O-6-methyldeoxyguanosine (O-6-medG) being the major mutagenic and cytotoxic DNA lesion. Critical to the prevention of colon cancer is the removal of O-6-medG DNA adducts, either through repair, for example, by O- 6-alkylguanine-DNA alkyltransferase (ATase) or targeted apoptosis. We repor t how rat colonocytes respond to administration of azoxymethane (a well-cha racterized experimental colon carcinogen and DNA-methylating agent) in term s of O-6-medG DNA adduct formation and adduct removal by ATase and apoptosi s. Our results are: (a) DNA damage is greater in actively proliferating cel ls than in the differentiated cell compartment; (b) expression of the DNA r epair enzyme ATase was not targeted to the proliferating cells or stem cell s but rather is confined primarily to the upper portion of the crypt; (c) a poptosis is primarily targeted to the stem cell and proliferative compartme nts; 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.