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Mice lacking the xeroderma pigmentosum group A gene (XPA؊/؊ mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA؊/؊ mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA؊/؊p53؉/؊ mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA؊/؊p53؉/؉ littermates. XPA؊/؊p53؊/؊ mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA؊/؊p53؉/؊ mice maintained the p53؉/؊ genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA؊/؊p53؉/؉ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency. p53 plays a complex and critical role in cellular proofreading in response to many stress signals including potentially oncogenic DNA damage.

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