Abstract
Exposure to ultraviolet (UV) light can cause significant damage to mammalian cells and, although the spectrum of damage produced varies with the wavelength of UV, all parts of the UV spectrum are recognised as being detrimental to human health. Characterising the cellular response to different wavelengths of UV therefore remains an important aim so that risks and their moderation can be evaluated, in particular in relation to the initiation of skin cancer. The p53 tumour suppressor protein is central to the cellular response that protects the genome from damage by external agents such as UV, thus reducing the risk of tumorigenesis. In response to a variety of DNA damaging agents including UV light, wild-type p53 plays a role in mediating cell-cycle arrest, facilitating apoptosis and stimulating repair processes, all of which prevent the propagation of potentially mutagenic defects. In this study we examined the induction of p53 protein and its influence on the survival of primary mouse fibroblasts exposed to different wavelengths of UV light. UVC was found to elevate p53 protein and its sequence specific DNA binding capacity. Unexpectedly, UVA treatment failed to induce p53 protein accumulation or sequence specific DNA binding. Despite this, UVA exposure of wild-type cells induced a p53 dependent G1 cell cycle arrest followed by a wave of p53 dependent apoptosis, peaking 12 hours post-insult. Thus, it is demonstrated that the elements of the p53 cellular response evoked by exposure to UV radiation are wavelength dependent. Furthermore, the interrelationship between various endpoints is complex and not easily predictable. This has important implications not only for understanding the mode of action of p53 but also for the use of molecular endpoints in quantifying exposure to different wavelengths of UV in the context of human health protection.
Highlights
Ultraviolet (UV) radiation constitutes only a fraction of the radiation emitted by the sun but it has a large impact on biological activity
The data presented here demonstrate that the time course, extent and biological consequences of p53 induction are dependent on the wavelength of the UV to which mammalian cells are exposed
The dose dependence of p53 accumulation in response to both UVB and UVC suggests that the degree of p53 induction may be directly related to the number of photoproducts in DNA
Summary
Ultraviolet (UV) radiation constitutes only a fraction of the radiation emitted by the sun but it has a large impact on biological activity. UV has become the subject of increasing concern and investigation due to depletion of the ozone layer and the continuing increase in the incidence of skin cancer. UVC (200– 290 nm) is largely prevented from reaching the surface of the Earth by its efficient absorption by ozone in the atmosphere. It is well documented that both the UVB and UVC wavelengths are strongly absorbed by DNA leading mainly to the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4 PP) [1]. The nature and amount of damage induced by UV radiation is wavelength dependent it is increasingly evident that both UVB and UVA can have significant deleterious effects on human health [4], [5]. UV radiation (UVB and UVA) has been classified as a Class I carcinogen by the International Agency for the Research on Cancer [6]
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