Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis

Like xeroderma pigmentosum (XP) patients, transgenic mice lacking nucleotid e excision repair (NER) genes such as XPA and XPC are extremely susceptible to ultraviolet (UV)-induced skin cancer, Because the p53 gene is an import ant target for UV carcinogenesis and because the p53 protein modulates NER, we investigated the consequences of NER deficiency on UV-induced p53 mutat ions in XPC-/- mouse skin tumors. Thirty-eight (76%) of 50 UV-induced XPC-/ - skin tumor analysed displayed C --> T or CC --> TT transitions at dipyrim idine sites on the untranscribed strand of the p53 gene. A major hot spot f or p53 mutation occurred at codon 270, which is also a hot spot in UV-induc ed skin tumors from NER-proficient C3H and SKH-hr 1 mice. Interestingly, co don 270 mutations were induced in both XPC-/- and +/+ mouse skin after 1 we ek of UV irradiation, but the mutations persisted only in XPC-/- mouse skin after 3-4 weeks of chronic UV, The persistence of UV-induced p53 mutations in XPC-/- mouse skin was associated with decreased apoptosis and increased proliferation of keratinocytes, suggesting that these events may contribut e to the accelerated development of UV-induced skin tumors in XPC-/- mice.