Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation

S Alekseev, H Kool, H Rebel, M Fousteri, J Moser, C Backendorf, FR de Gruijl, H Vrieling*, LHF Mullenders

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

60 Citations (Scopus)

Abstract

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 UVDDB, 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.

Original languageEnglish
Pages (from-to)10298-10306
Number of pages9
JournalCancer Research
Volume65
Issue number22
DOIs
Publication statusPublished - 15-Nov-2005

Keywords

  • DNA-BINDING-PROTEIN
  • CYCLOBUTANE PYRIMIDINE DIMERS
  • NUCLEOTIDE EXCISION-REPAIR
  • PIGMENTOSUM GROUP-E
  • TRANSCRIPTION-COUPLED REPAIR
  • GLOBAL GENOMIC REPAIR
  • XERODERMA-PIGMENTOSUM
  • DAMAGED-DNA
  • INDUCED APOPTOSIS
  • COCKAYNE-SYNDROME

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