Cytotoxic, mutagenic and carcinogenic properties of ultraviolet radiation : shining light on photolesions
Year: 2003
Type: dissertation
Abstract: Exposure to ultraviolet light (UV light) poses a serieus threat to human health. An altered life style \n(holidays in the sun, tanning devices) has led to increased exposure to UV light in the Western \npopulation. UV light damages the DNA, the carrier of genetic information, which can result in \npermanent alterations in the genome and, ultimately, cancer. The majority of the DNA lesions induced \nby UV light consists of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone \nphotoproducts (6-4PPs). The relative contribution of these CPDs and 6-4PPs to the effects of acute \nand chronic UV exposure, however, is nat known (e.g. sunburn, cancer). Although organisms are \nequipped with the nucleotide excision repair (NER) mechanism for remaval of lesions, this mechanism \nmay nat offer sufficient proteetion in cases of excessive exposure to UV light. The aim of this thesis is \nto further elucidate the mechanisms behind the detrimental effects of UV exposure and to determine \nthe role of individual classes of UV-induced DNA lesions in these processes. To this end, we generated \nmice transgenically expressing photolyase enzymes. This approach enables light-controlled remaval of \na single type of lesion, allowing investigation of the contribution of individual lesions to UV responses. \nIn Chapter 1, we review the current knowledge on UV-induced DNA damage and repair, and the \nconsequences of UV exposure on human health. Chapters 2 and 3 describe the generation of \nubiquitously expressing CPD and 6-4PP photolyase transgenie mice. We show that these marsupial and \nplant photolyase gene products are functional in mice, resulting in light-dependent remaval of DNA \nlesions from mouse skin. Furthermore, we provide evidence that CPDs are responsible for adverse UV \neffects including cell death, sunburn and permanent genomic alterations (mutations). In Chapter 4 \nwe describe the generation of transgenie mice expressing photolyase from the keratinocyte-specific \nK14 promoter, allowing fast remaval of DNA damage by photoreactivation in basal keratinocytes of the \nepidermis, whereas in other cell types such as fibroblasts and Langerhans cells lesions are repaired \nin slow fashion (if at all). This gave us the unique opportunity to dissect the cell types involved in \nUV responses. In Chapter 5 the carcinogenic potential
Author: Judith Jans
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1580101692