Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions.
Mouse models that mimic the human skin cancer-prone disease xeroderma pigmentosum (XP) provide an useful experimental system with which to study the relationship between the DNA repair process of nucleotide excision repair (NER) and ultraviolet- (UV) induced skin carcinogenesis. We have generated Xpc mutant mice and documented their deficiency in the process of NER of UV-induced DNA damage. Xpc mutant mice are highly predisposed to UV-B radiation-induced skin cancer, both in the homozygous and the heterozygous state. The combination of Xpc and Trp53 mutations enhances this predisposition and alters the tumor spectrum observed in single mutant mice. These results suggest a synergism between NER and the function of Trp53 in suppression of cancer. We have examined the mutational spectrum in the Trp53 gene from skin cancers in Trp53+/+ and Trp53+/- mice of all three Xpc genotypes and have found evidence for signature mutations associated with defective NER. In addition, we have demonstrated that Xpc mutant mice are highly predisposed to the induction of lung and liver cancers by treatment with 2-acetylaminofluorene (2-AAF) and N-OH-2-AAF. By combining the Xpc mutation with other mutations in genes involved in repair of DNA damage we have identified additional genetic interactions important in carcinogenesis. The mouse Apex gene is a critical component of the base excision repair (BER) pathway as well as the redox regulation of transcription factors important in growth control and the cellular response to DNA damage. By combining mutations in Xpc, Trp53 and Apex we have obtained genetic evidence for a functional interaction between Apex and Trp53 which probably involves the activation of the Trp53 protein by Apex. Mutations in the mismatch repair (MMR) gene Msh2 also influence the carcinogenesis observed in Xpc Trp53 mutant mice. Our results demonstrate that multiple repair pathways operate in prevention of tumor formation.
Meira
L B
LB
Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Reis
A M
AM
Cheo
D L
DL
Nahari
D
D
Burns
D K
DK
Friedberg
E C
EC
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004260:DNA Repair; D004195:Disease Models, Animal; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000235:genetics
D002273:Carcinogens; D015073:2-Acetylaminofluorene