Powerful skin cancer protection by a CPD-photolyase transgene.
BACKGROUND
The high and steadily increasing incidence of ultraviolet-B (UV-B)-induced skin cancer is a problem recognized worldwide. UV introduces different types of damage into the DNA, notably cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs). If unrepaired, these photolesions can give rise to cell death, mutation induction, and onset of carcinogenic events, but the relative contribution of CPDs and 6-4PPs to these biological consequences of UV exposure is hardly known. Because placental mammals have undergone an evolutionary loss of photolyases, repair enzymes that directly split CPDs and 6-4PPs into the respective monomers in a light-dependent and lesion-specific manner, they can only repair UV-induced DNA damage by the elaborate nucleotide excision repair pathway.


RESULTS
To assess the relative contribution of CPDs and 6-4PPs to the detrimental effects of UV light, we generated transgenic mice that ubiquitously express CPD-photolyase, 6-4PP-photolyase, or both, thereby allowing rapid light-dependent repair of CPDs and/or 6-4PPs in the skin. We show that the vast majority of (semi)acute responses in the UV-exposed skin (i.e., sunburn, apoptosis, hyperplasia, and mutation induction) can be ascribed to CPDs. Moreover, CPD-photolyase mice, in contrast to 6-4PP-photolyase mice, exhibit superior resistance to sunlight-induced tumorigenesis.


CONCLUSIONS
Our data unequivocally identify CPDs as the principal cause of nonmelanoma skin cancer and provide genetic evidence that CPD-photolyase enzymes can be employed as effective tools to combat skin cancer.
Jans
Judith
J
Department of Genetics, Medical Genetics Center, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, Post Office Box 1738, 3000 DR Rotterdam, The Netherlands.
Schul
Wouter
W
Sert
Yurda-Gul
YG
Rijksen
Yvonne
Y
Rebel
Heggert
H
Eker
Andre P M
AP
Nakajima
Satoshi
S
van Steeg
Harry
H
de Gruijl
Frank R
FR
Yasui
Akira
A
Hoeijmakers
Jan H J
JH
van der Horst
Gijsbertus T J
GT
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002277:Carcinoma / Q000209:etiology* / Q000517:prevention & control; D002460:Cell Line; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics*; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D011740:Pyrimidine Dimers / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000209:etiology* / Q000517:prevention & control; D014466:Ultraviolet Rays
D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer; D004255:Deoxyribodipyrimidine Photo-Lyase