Powerful skin cancer protection by a CPD-photolyase transgene.

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.

• Authors: 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
• Journal: Current biology : CB (Curr Biol) Vol. 15 Issue 2 Pg. 105-15 (Jan 26 2005) ISSN: 0960-9822 [Print] England
• PMID: 15668165 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrimidine Dimers
• pyrimidine-pyrimidone dimer
• Deoxyribodipyrimidine Photo-Lyase

Topics

• Animals
• Apoptosis (radiation effects)
• Carcinoma (etiology, prevention & control)
• Cell Line
• DNA Damage (radiation effects)
• DNA Repair (genetics)
• Deoxyribodipyrimidine Photo-Lyase (genetics, metabolism)
• Gene Expression
• Mice
• Mice, Transgenic
• Pyrimidine Dimers (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin Neoplasms (etiology, prevention & control)
• Ultraviolet Rays