Cytotoxic, mutagenic and carcinogenic properties of ultraviolet radiation : shining light on photolesions

textabstractExposure to ultraviolet light (UV light) poses a serieus threat to human health. An altered life style (holidays in the sun, tanning devices) has led to increased exposure to UV light in the Western population. UV light damages the DNA, the carrier of genetic information, which can result in permanent alterations in the genome and, ultimately, cancer. The majority of the DNA lesions induced by UV light consists of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone photoproducts (6-4PPs). The relative contribution of these CPDs and 6-4PPs to the effects of acute and chronic UV exposure, however, is nat known (e.g. sunburn, cancer). Although organisms are equipped with the nucleotide excision repair (NER) mechanism for remaval of lesions, this mechanism may nat offer sufficient proteetion in cases of excessive exposure to UV light. The aim of this thesis is to further elucidate the mechanisms behind the detrimental effects of UV exposure and to determine the role of individual classes of UV-induced DNA lesions in these processes. To this end, we generated mice transgenically expressing photolyase enzymes. This approach enables light-controlled remaval of a single type of lesion, allowing investigation of the contribution of individual lesions to UV responses. In Chapter 1, we review the current knowledge on UV-induced DNA damage and repair, and the consequences of UV exposure on human health. Chapters 2 and 3 describe the generation of ubiquitously expressing CPD and 6-4PP photolyase transgenie mice. We show that these marsupial and plant photolyase gene products are functional in mice, resulting in light-dependent remaval of DNA lesions from mouse skin. Furthermore, we provide evidence that CPDs are responsible for adverse UV effects including cell death, sunburn and permanent genomic alterations (mutations). In Chapter 4 we describe the generation of transgenie mice expressing photolyase from the keratinocyte-specific K14 promoter, allowing fast remaval of DNA damage by photoreactivation in basal keratinocytes of the epidermis, whereas in other cell types such as fibroblasts and Langerhans cells lesions are repaired in slow fashion (if at all). This gave us the unique opportunity to dissect the cell types involved in UV responses. In Chapter 5 the carcinogenic potential of DNA lesions are studied. Importantly, we show that remaval of CPDs alone is sufficient to delay the induction of skin cancer to a great extent. An important role in UV-induced skin carcinogenesis is performed by the immune system. We show that CPD remaval not only protects the animal from cancer by lowering the mutation laad, but it also abclishes UV-induced immunosuppression, allowing the immune system to respond adequately to malignancies. The results described in this thesis are reviewed in a general discussion in Chapter 6.