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 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. Analogous to human XPC cells, embryonic fibroblasts from XPC knockout mice are only capable of performing transcription coupled repair of DNA photolesions. We show that these XPC knockout mice, in striking contrast to XPA knockout mice, do not have a lower minimal erythema/edema dose than their wild-type littermates. Hence, defective global genome repair appears to lead to skin cancer susceptibility, but does not influence the sensitivity to acute effects of UVB radiation, such as erythema and edema. The latter phenomena thus relate to the capacity to perform transcription coupled repair, which suggests that blockage of RNA synthesis is a key event in the development of UV erythema and edema.
Berg
R J
RJ
Department of Dermatology, University Hospital Utrecht, The Netherlands.
Ruven
H J
HJ
Sands
A T
AT
de Gruijl
F R
FR
Mullenders
L H
LH
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D004487:Edema / Q000209:etiology; D004890:Erythema / Q000209:etiology; D020022:Genetic Predisposition to Disease; D016678:Genome; D051379:Mice / Q000196:embryology / Q000235:genetics; D018345:Mice, Knockout; D010787:Photosensitivity Disorders / Q000235:genetics; D011740:Pyrimidine Dimers / Q000737:chemistry / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D011740:Pyrimidine Dimers