In vitro and in vivo analysis of the XPA gene

Nucleotide excision repair (NER) is a versatile repair system capable of rectifying a broad spectrum of DNA damage. The importance of NER has been suggested by studies of the human inherited disease, xeroderma pigmentosum (XP), which is characterized by a high incidence of skin cancer in sun-exposed areas. Cells from XP patients are hypersensitive to killing by UVirradiation and have a defect in the early steps of NER processes. There are seven different complementation groups (groups A through G) in XP. We examined the roles of the group A XP (XPA) gene and its product in NER and prevention of carcinogen-induced tumorigenesis. The XPA gene encodes a protein of 273 amino acids with C4 type zinc finger motif, and the XPA protein preferentially bound to DNA damaged by UV, cisplatin or osmium tetroxide, indicating that the XPA protein is involved in the damage recognition step of NER processes. Moreover, the XPA protein has an ability to interact with other proteins. We found that the 34 kDa subunit of replication protein A (RPA) and DNA repair protein ERCC1 bound to the XPA protein. Biological significance of these interactions will be discussed. To elucidate the in vivo function of the XPA gene and molecular basis of group A XP phenotype, we established X/M-deficient mice using mouse ES cell techniques. The XPAdeficient mice were defective in NER process and highly susceptible to UV-induced tumorigenesis. The X/M-deficient mice provide a good in vivo model to study UV-induced skin carcinogenesis in group A XP patients.