ALKYLTRANSFERASE TRANSGENIC MICE - PROBES OF CHEMICAL CARCINOGENESIS

Transgenic mice expressing DNA-repair genes are an instructive model w ith which to study the protective role of DNA-repair pathways in both spontaneous and chemical carcinogenesis. Of particular interest in che mical carcinogenesis is the DNA-repair protein O-6-alkylguanine-DNA al kyltransferase (alkyltransferase) which repairs O-6-aIkylguanine-DNA a dducts. Transgenic mice carrying expression constructs for the alkyltr ansferase gene - either the human MGMT cDNA or the bacterial ada gene - express increased levels of alkyltransferase and have increased capa city to remove O-6-methylguanine-DNA adducts. Protection from the DNA damaging effects of N-nitroso compounds occurs specifically in the cel ls and tissues in which the alkyltransferase transgene is expressed. F or instance, mice carrying the PEPCKada construct have increased alkyl transferase in the liver and more rapid removal of O(6)methylguanine-D NA adducts. The protective effect is noted in hepatocytes, which expre ss PEPCK-Iinked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various model s include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human alkyltransferase in the thymus have a reduced inc idence of thymic lymphomas following exposure to methyl nitrosourea (M NU), evidence of a role for this DNA-repair protein in protection from carcinogenesis due to N-nitroso compounds. Protection has also been o bserved in the induction of hepatic tumors by N-nitroso-dimethylamine (NDMA). These models will be used to identify whether overexpression o f a single DNA-repair gene can block the carcinogenic process of N-nit roso compounds in many different tissues.