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 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.
Hong
M Y
MY
Faculty of Nutrition, Texas A & M University, College Station 77843-2471, USA.
Chapkin
R S
RS
Wild
C P
CP
Morris
J S
JS
Wang
N
N
Carroll
R J
RJ
Turner
N D
ND
Lupton
J R
JR
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002451:Cell Compartmentation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology; D004247:DNA / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D002273:Carcinogens; D004247:DNA; D019883:Alkyl and Aryl Transferases; C050956:DNA alkyltransferase; D001397:Azoxymethane