Defective Global Genome Repair in XPC Mice Is Associated with Skin Cancer Susceptibility But Not with Sensitivity to UVB Induced Erythema and Edema (original) (raw)

1998, Journal of Investigative Dermatology

It is generally presumed that xeroderma pigmentosum (XP) patients are extremely sensitive to developing UV erythema, and that they have a more than 1000-fold increased skin cancer risk. Recently established mouse 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 UVB induced squamous cell carcinomas. In XPA knockouts, nucleotide excision repair of UV induced DNA photolesions is completely defective (i.e., both global genome repair and transcription coupled repair are defective). We determined the strand specific removal of cyclobutane pyrimidine dimers and pyrimidine [6-4] pyrimidone photoproducts from the p53 gene in cells from XPC knockout mice and wild-type littermates. S unburn is a UV induced inflammatory reaction that is characterized by cutaneous vasodilatation (erythema), and that can be followed by an increase in vascular permeability with exudation of fluid (edema) in the affected skin. The pathway leading to sunburn is most commonly thought to be activated by UV induced DNA damage. The evidence that supports a linkage between DNA damage and sunburn is that genetic diseases with defects in the removal of UV photoproducts, such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS), are accompanied by increased sensitivity to sunburn (Cleaver and Kraemer, 1989; Bootsma, 1993). In addition, it has been shown in the opossum Monodelphis domestica that immediate removal of UV photoproducts by photoreactivation leads to a suppression of the erythemal response (Ley, 1985). Furthermore, the wavelengths that are the most effective in producing UV photolesions (namely, the UVB region) are also the most effective in producing erythema (Hacham et al, 1991) or edema (Johnson, 1978). The mechanism that connects DNA damage to the inflammatory reaction is unclear. UVB induced DNA damage may Manuscript