Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice.
The nucleotide excision repair (NER) system is comprised of two subpathways, i.e., transcription-coupled repair (TCR) and global genome repair (GGR). To establish the relative importance of TCR and GGR for UV effects on the skin, we have used hairless knockout mouse strain lacking either TCR (CSB -/-) or GGR (XPC -/-). In single exposure experiments, we found that CSB -/- mice have a 7-16 times higher susceptibility to sunburn than XPC -/- mice and than heterozygous (+/-) and wild-type (+/+) controls. Exposure to 80 J/m2 UV radiation (i.e., suberythemogenic in CSB -/-) on 10 consecutive days gives rise to epidermal hyperplasia in CSB -/- and XPC -/-, whereas repair-proficient controls do not show epidermal hyperplasia from these exposures. In addition, CSB -/- mice develop marked parakeratosis, whereas XPC -/- mice and controls do not. Under continued exposure to this daily dose, squamous cell carcinomas appear in CSB -/-, XPC -/-, and in the control groups, whereas only in the CSB -/- animals is a fairly high number of benign papillomas also found. The median latency time of squamous cell carcinomas (diameters > or = 1 mm) is 84 days for the XPC -/- mice, 115 days for the CSB -/- mice, and 234-238 days for the heterozygous and wild-type control groups. These results indicate that GGR is more important than TCR in protection against UV-induced carcinomas of the skin but not against other UV effects such as sunburn, epidermal thickening, scaling of the stratum corneum, and development of papillomas. These results also indicate that GGR capacity may serve as a better predictor for skin cancer susceptibility than sensitivity to sunburn. The relative cancer susceptibilities of GGR- and TCR-deficient skin could well depend on the balance between an increased mutation rate and the presence (in CSB -/-) or lack (in XPC -/-) of a compensatory apoptotic response.
Berg
R J
RJ
Department of Dermatology, University Medical Center Utrecht, The Netherlands.
Rebel
H
H
van der Horst
G T
GT
van Kranen
H J
HJ
Mullenders
L H
LH
van Vloten
W A
WA
de Gruijl
F R
FR
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics; D004260:DNA Repair; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D005091:Exons; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics; D010212:Papilloma / Q000209:etiology / Q000235:genetics; D010241:Parakeratosis / Q000209:etiology / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D013471:Sunburn / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D014466:Ultraviolet Rays