Alkyltransferase transgenic mice: probes of chemical carcinogenesis

Abstract

Transgenic mice expressing DNA-repair genes are 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 O 6-alkylguanine-DNa alkyltransferase (alkyltransferase) which repairs O 6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the alkyltransferase gene — either the human MGMT cDNDA or the bacterial ada gene — express increased levels of alkyltransferase and have increased capacity to remove O 6-methylguanine-DNA adducts. Protection from DNA damaging effects of N-nitroso compounds occurs specifically in the cells in tissues in which the alkyltransferase transgene is expressed. For instance, mice carrying the PECK ada construct have increased alkyltransferase in the liver and more rapid removal of O 6-methylguanine-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 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.