The long-term objectives of this proposal are to investigate the relationship of defective repair of DNA damage to cancer in humans. To this end mutational inactivation of various DNA repair genes in mice by targeted gene replacement is being used as an experimental strategy. A mouse strain has been generated which carries homozygous deletions in the nucleotide excision repair (NER) gene XPC. This strain is exceptionally prone to ultraviolet (UV) radiation-induced skin cancer. Experiments are in progress to determine predisposition to liver cancer associated with exposure to the liver carcinogen 2-acetylaminofluorene, the repair of which requires the process of NER in mammals. XPC-1- mice that are additionally heterozygously or homozygously defective in the p53 tumor suppresser gene exhibit an even greater predisposition of skin cancer. Studies are proposed to investigate the mechanism of this synergistic interaction, in particular whether abrogation of the G1->S checkpoint function or of the apoptotic function of the p53 gene (or both), mediates this effect. Dr. Friedberg will generate a mouse strain by targeted gene replacement that is homozygous defective in the HAP1 gene which encodes the major apurinic/apyrimidinic (AP) endonuclease required for the process of base excision repair (BER) in mice. Such a mutant mouse is expected to be defective in the repair of various types of spontaneous base damage in DNA, particularly that generated by oxidative metabolism. Crosses will be made between the XPC-1- (NER-defective) mouse, the HAP1-/- (BER-defective) mouse and mice defective in the mismatch repair defective mouse MSH2, in order to investigate the role of all three known excision repair pathways in both spontaneous and environmental carcinogen-induced cancer in mammals.
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