DEFECTIVE GLOBAL GENOME REPAIR IN XPC MICE IS ASSOCIATED WITH SKIN-CANCER SUSCEPTIBILITY BUT NOT WITH SENSITIVITY TO UVB INDUCED ERYTHEMA AND EDEMA

It is generally presumed that xeroderma pigmentosum (XP) patients are extremely sensitive to developing UV erythema, and that they have a mo re than 1000-fold increased skin cancer risk, Recently established mou se models for XP can be employed to investigate the mechanism of these increased susceptibilities. In line with human data, both XPA and XPC knockout mice have been shown to have an increased susceptibility to WB induced squamous cell carcinomas, In XPA knockouts, nucleotide exci sion repair of UV induced DNA photolesions is completely defective (i. e., both global genome repair and transcription coupled repair are def ective). We determined the strand specific removal of cyclobutane pyri midine dimers and pyrimidine [6-4] pyrimidone photoproducts front the p53 gene in cells from XPC knockout mice and wild-type littermates, An alogous to human XPC cells, embryonic fibroblasts from XPC knockout mi ce are only capable of performing transcription coupled repair of DNA photolesions. We show that these XPC knockout mice, in striking contra st to XPA knockout mice, do not have a lower minimal erythema/edema do se than their wild-type littermates, Hence, defective global genome re pair appears to lead to skin cancer susceptibility, but does not influ ence the sensitivity to acute effects of UVB radiation, such as erythe ma and edema, The latter phenomena thus relate to the capacity to perf orm transcription coupled repair, which suggests that blockage of RNA synthesis is a key event in the development of UV erythema and edema.