Exposure 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 potentia
