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Enzyme, lost in most mammals, is shown to protect against UV-induced skin cancer


In a finding that broadens our insight into the cause of certain kinds of UV-induced skin cancer, researchers at Erasmus University Medical Center (Rotterdam, The Netherlands) have employed an evolutionarily ancient enzyme-repair system to identify the principal type of DNA damage responsible for the onset of skin-tumor development. The researchers’ findings also suggest that this enzyme system may be useful in developing preventative therapies against skin cancer.

Ultraviolet light is a known source of damage to our DNA, but under normal conditions humans and other mammals are capable of removing UV-induced DNA damage by a DNA repair mechanism called nucleotide excision repair. Insufficient repair of UV-induced DNA damage, which for example may occur after excessive unprotected sunbathing, can lead to cellular death – recognized as sunburn of the skin – and may cause permanent changes in the DNA (mutations) that ultimately can result in the onset of skin cancer. Thus far it was not clear how the two major types of UV-induced DNA lesions – cyclobutane pyrimidine dimers (CPDs) and (6-4)photoproducts (6-4PPs) – contribute to the processes of cell death and cancer formation. Identifying the relative contributions of the two types of damage to tumor formation is critical for the development of therapies that could help prevent skin cancer. Moreover, CPDs and 6-4PPs have particular potential to cause lasting damage to mammalian cells because photolyases – a class of enzymes capable of efficiently repairing these lesions – have apparently been lost from placental mammals over the course of evolution.

Thus, most mammals, including humans, can only repair these lesions through a much less direct and elaborate process called nucleotide excision repair.

In the new work, Dr. Bert van der Horst and colleagues studied the effects of CPD and 6-4PP lesions by providing mice with transgenes encoding CPD and 6-4PP photolyase enzymes.

Although mice do not ordinarily produce these enzymes, which remove either CPD or 6-4PP lesions by using visible light as an energy source, expression of the transgenes allowed rapid photolyase-mediated repair of these lesions. The researchers found that transgenic mice bearing the CPD photolyase transgene, in contrast to mice bearing the 6-4PP photolyase transgene, showed superior resistance to the deleterious effects of UV irradiation. Not only could CPD photolyase transgenic animals withstand doses of UV light that cause severe sunburn in normal mice, but they also showed superior resistance to UV-induced skin cancer. This work clearly points to CPD lesions as the major intermediate in UV-induced cellular damage leading to non-melanoma skin cancer. Importantly, it also suggests that photolyases may be successfully employed as a genetic tool to combat UV-induced skin cancer.

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: "Powerful Skin Cancer Protection by a CPD-Photolyase Transgene"

The other members of the research team include Judith Jans of Erasmus University Medical Center, Rotterdam, presently at University of California, Berkeley; Wouter Schul of Erasmus University Medical Center, Rotterdam and Tohoku University; Yurda-Gul Sert, Yvonne Rijksen, Andre P.M. Eker, Jan H.J. Hoeijmakers, and Gijsbertus T.J. van der Horst of Erasmus University Medical Center, Rotterdam; Heggert Rebel and Frank R. de Gruijl of Leiden University Medical Center; Satoshi Nakajima of Novartis, Institute of Tropical Disease, Singapore; Harry van Steeg of National Institute of Public Health and the Environment in Bilthoven, The Netherlands; and Akira Yasui of Tohoku University. This work was supported by the Dutch Cancer Foundation, the Association for International Cancer Research, and the Japanese Ministry of Education, Science, and Culture.

Heidi Hardman | EurekAlert!
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