Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc-dependent DNA repair process

• Published in: DNA repair 2004-04, Vol.3 (4), p.379-386
• Main Authors: Nahari, Dorit, McDaniel, Lisa D, Task, Laurie B, Daniel, Russell L, Velasco-Miguel, Susana, Friedberg, Errol C
• Format: Article
• Language: English
• Subjects: Animals; Bacteriology; Base Sequence; Biological and medical sciences; Codon; DNA Primers; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Genes, p53; Growth, nutrition, cell differenciation; Mice; Mice, Mutant Strains; Microbiology; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; Mutation; Mutation detection; Mutational hot spots; NER; p53 gene; Ultraviolet Rays; Xpc mice
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2003.03.001

Mutational hot spots in the human p53 gene are well established in tumors in the human population and are frequently negative prognosticators of the clinical outcome. We previously developed a mouse model of skin cancer with mutations in the xeroderma pigmentosum group C gene ( Xpc) . UVB radiation-induced skin cancer is significantly enhanced in these mice when they also carry a mutation in one copy of the Trp53 gene ( Xpc −/− Trp53 +/−). Skin tumors in these mice often contain inactivating mutations in the remaining Trp53 allele and we have previously reported a novel mutational hot spot at a non-dipyrimidine site (ACG) in codon 122 of the Trp53 gene in the tumors. Here we show that this mutation is not a hot spot in Xpa or Csa mutant mice. Furthermore, the mutation in codon T122 can be identified in mouse skin DNA from ( Xpc −/− Trp53 +/−) mice as early as 2 weeks after exposure to UVB radiation, well before histological evidence of dysplastic or neoplastic changes. Since this mutational hot spot is not at a dipyrimidine site and is apparently Xpc-specific, we suggest that some form of non-dipyrimidine base damage is normally repaired in a manner that is distinct from conventional nucleotide excision repair, but that requires XPC protein.