Transgenic mice expressing DNA-repair genes are an instructive model with which to study the protective role of DNA-repair pathways in both spontaneous and chemical
carcinogenesis. Of particular interest in chemical
carcinogenesis is the DNA-repair
protein O6-alkylguanine-DNA
alkyltransferase (
alkyltransferase) which repairs O6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the
alkyltransferase gene--either the human MGMT
cDNA or the bacterial ada gene--express increased levels of
alkyltransferase and have increased capacity to remove O6-methylguanine-DNA adducts. Protection from the
DNA damaging effects of N-
nitroso compounds occurs specifically in the cells and tissues in which the
alkyltransferase transgene is expressed. For instance, mice carrying the PEPCKada construct have increased
alkyltransferase in the liver and more rapid removal of O6methylguanine-DNA adducts. The protective effect is noted in hepatocytes, which express PEPCK-linked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various models include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human
alkyltransferase in the thymus have a reduced incidence of thymic
lymphomas following exposure to methyl nitrosourea (MNU), evidence of a role for this DNA-repair
protein in protection from
carcinogenesis due to N-
nitroso compounds. Protection has also been observed in the induction of hepatic
tumors by N-nitroso-
dimethylamine (NDMA). These models will be used to identify whether overexpression of a single DNA-repair gene can block the carcinogenic process of N-
nitroso compounds in many different tissues.