Defective nucleotide excision repair in Xpc mutant mice and its association with cancer predisposition

Mice that are genetically engineered are becoming increasingly more powerfu l tools for understanding the molecular pathology of many human hereditary diseases, especially those that confer an increased predisposition to cance r. We have generated mouse strains defective in the Xpc gene, which is requ ired for nucleotide excision repair (NER) of DNA. Homozygous mutant mice ar e highly prone to skin cancer following exposure to WE radiation, and to li ver and lung cancer following exposure to the chemical carcinogen acetylami nofluorene (AAF). Skin cancer predisposition is significantly augmented whe n mice are additionally defective in Trp53 (p53) gene function. We also pre sent the results of studies with mice that are heterozygous mutant in the A pex (Hap1, Ref-1) gene required for base excision repair and with mice that are defective in the mismatch repair gene Msh2. Double and triple mutant m ice mutated in multiple DNA repair genes have revealed several interesting overlapping roles of DNA repair pathways in the prevention of mutation and cancer. (C) 2000 Elsevier Science B.V. All rights reserved.