Powerful skin cancer protection by a CPD-photolyase transgene

Judith Jans, Wouter Schul, Yurda Gul Sert, Yvonne Rijksen, Heggert Rebel, Andre P.M. Eker, Satoshi Nakajima, Harry Van Steeg, Frank R. De Gruijl, Akira Yasui, Jan H.J. Hoeijmakers, Gijsbertus T.J. Van Der Horst

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    132 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)105-115
    Number of pages11
    JournalCurrent Biology
    Volume15
    Issue number2
    DOIs
    Publication statusPublished - 2005 Jan 26

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)

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  • Cite this

    Jans, J., Schul, W., Sert, Y. G., Rijksen, Y., Rebel, H., Eker, A. P. M., Nakajima, S., Van Steeg, H., De Gruijl, F. R., Yasui, A., Hoeijmakers, J. H. J., & Van Der Horst, G. T. J. (2005). Powerful skin cancer protection by a CPD-photolyase transgene. Current Biology, 15(2), 105-115. https://doi.org/10.1016/j.cub.2005.01.001