Characterization of the T122L Mutation in p53 and its Protein Product in Xpc Mutant Mice

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Xeroderma Pigmentosum (XP) is a rare genetic disorder characterized by extreme sensitivity to sunlight, and a profound predisposition to skin cancer due to defects in nucleotide excision repair (NER) of DNA. XP patients can be divided into seven complementation groups (A-G) with corresponding genes Xpa thru Xpg. I have studied a novel UV-induced hot spot in codon 122 of the p53 gene in mice deficient in XPC protein and heterozygous for the p53 gene. The original Threonine residue is mutated to Leucine as a result of an AC->TT change. The main goal of this work was to characterize the T122L mutation and its protein product, and to elucidate the mechanism(s) that affect its appearance in XPC deficient skin. I have shown that the T122L mutation is rare in other NER deficient mouse models, suggesting that the XPC protein is required specifically to repair the unidentified damage in this codon. In addition, I have shown that the T122L mutant protein is not a loss of function mutant, but it retains some wild type protein functions including ransactivation of p53 regulated genes and promotion of cell cycle arrest in response to UV-induced DNA damage. The altered transactivation properties of the mutant protein might support clonal expansion, giving cells that express it a growth advantage. In order to determine whether the p53 mutant protein function contributes significantly to the elevated mutation frequency observed in XPC deficient mice I have used a p53 knockout mouse model that retains the genomic region containing codon 122 without expressing p53 protein. I show that the mutation is observed in low frequencies in mice that do not express protein, suggesting that repair deficiency is the key factor for the appearance of the T122L mutation. However, once the mutation is formed its frequency is significantly increased as a result of the mutant protein function. The specific requirement for XPC protein and the location of the damage at a nondipyrimidine nucleotide site hints at an additional role of XPC in a repair pathway different from NER.