Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation.
UV-damaged DNA-binding protein (UV-DDB) is essential for global genome repair (GGR) of UV-induced cyclobutane pyrimidine dimers (CPD). Unlike human cells, rodent epidermal cells are deficient in GGR of CPDs and express a subunit of UV-DDB, DDB2, at a low level. In this study, we generated mice (K14-DDB2) ectopically expressing mouse DDB2 at elevated levels. Enhanced expression of DDB2 both delayed the onset of squamous cell carcinoma and decreased the number of tumors per mouse in chronically UV-B light-exposed hairless mice. Enhanced expression of DDB2 improved repair of both CPDs and pyrimidine(6-4)pyrimidone photoproducts (6-4PP) in dermal fibroblasts. However, GGR of CPDs in K14-DDB2 mice did not reach the level of efficiency of human cells, suggesting that another repair protein may become rate limiting when DDB2 is abundantly present. To complement these studies, we generated mice in which the DDB2 gene was disrupted. DDB2-/- and DDB2+/- mice were found to be hypersensitive to UV-induced skin carcinogenesis. On the cellular level, we detected a delay in the repair of 6-4PPs in DDB2-/- dermal fibroblasts. Neither the absence nor the enhanced expression of DDB2 affected the levels of UV-induced apoptosis in epidermal keratinocytes or cultured dermal fibroblasts. Our results show an important role for DDB2 in the protection against UV-induced cancer and indicate that this protection is most likely mediated by accelerating the repair of photolesions.
Alekseev
Sergey
S
Department of Toxicogenetics, Leiden University Medical Center, Leiden University, Leiden, the Netherlands.
Kool
Hanneke
H
Rebel
Heggert
H
Fousteri
Maria
M
Moser
Jill
J
Backendorf
Claude
C
de Gruijl
Frank R
FR
Vrieling
Harry
H
Mullenders
Leon H F
LH
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D009842:Oligopeptides; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism; D011836:Radiation Tolerance / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D009842:Oligopeptides; D010455:Peptides; D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer; C085706:FLAG peptide