Decreased UV sensitivity, mismatch repair activity and abnormal cell cyclecheckpoints in skin cancer cell lines derived from UVB-irradiated XPA-deficient mice

Xeroderma pigmentosum group A gene (XPA)-deficient mice are defective in nu cleotide excision repair (NER) and are therefore highly sensitive to ultrav iolet (UV)-induced skin carcinogenesis. We established cell lines from skin cancers of WE-irradiated XPA-deficient mice to investigate the phenotypic changes occurring during skin carcinogenesis. As anticipated, the skin canc er cell lines were devoid of NER activity but were less sensitive to killin g by UV-irradiation than the XPA(- / -) fibroblast cell line. The lines wer e also more resistant to B-thioguanine (6-TG) than XPA(- / -) and XPA( + / +) fibroblasts, which was suggestive of a mismatch repair (MMR) defect. Ind eed, in vitro mismatch binding and MMR activity were impaired in several of these cell lines. Moreover, these cell lines displayed cell cycle checkpoi nt derangements following UV-irradiation and 6-TG exposure. The above findi ngs suggest that MMR downregulation may help cells escape killing by UVB, a s was seen previously for methylating agents and cisplatin, and thus that M MR deficient clones are selected for during the tumorigenic transformation of XPA(- / -) cells. (C) 2000 Elsevier Science B.V, All rights reserved.