Differential activity of UV-DDB in mouse keratinocytes and fibroblasts: impact on DNA repair and UV-induced skin cancer.
UV-damaged DNA-binding protein (UV-DDB) is essential for global genome nucleotide excision repair of UV-induced cyclobutane pyrimidine dimers (CPD) and accelerates repair of 6-4 photoproducts (6-4PP). The high UV-induced skin cancer susceptibility of mice compared to man has been attributed to low expression of the UV-DDB subunit DDB2 in mouse skin cells. However, DDB2 knockout mice exhibit enhanced UVB skin carcinogenesis indicating that DDB2 protects mice against UV-induced skin cancer. To resolve these apparent contradictory findings, we systematically investigated the NER capacity of mouse fibroblasts and keratinocytes. Compared to fibroblasts, keratinocytes exhibited an increased level of UV-DDB activity, contained significantly higher levels of other NER proteins (i.e. XPC and XPB) and displayed efficient repair of CPD. At low UVB dosages, the difference in skin cancer susceptibility between DDB2 KO and wild type mice was even much more pronounced than previously reported with high dose UVB exposures. Hence, our observations show that mouse keratinocytes express sufficient levels of UV-DDB for efficient repair of photolesions and efficient protection against UV-induced skin cancer at physiological relevant UV exposure.
Pines
Alex
A
Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Backendorf
Claude
C
Alekseev
Sergey
S
Jansen
Jacob G
JG
de Gruijl
Frank R
FR
Vrieling
Harry
H
Mullenders
Leon H F
LH
D000818:Animals; D004260:DNA Repair / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D008812:Mice, Hairless; D011740:Pyrimidine Dimers / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D011740:Pyrimidine Dimers