Abstract
The epidermis is a self-renewal epithelium continuously exposed to the genotoxic effects of ultraviolet (UV) light, the main cause of skin cancer. Therefore, it needs robust self-protective mechanisms facing genomic damage. p53 has been shown to mediate apoptosis in sunburn cells of the epidermis. However, epidermal cells daily receive sublethal mutagenic doses of UV and massive apoptosis would be deleterious. We have recently unravelled an anti-oncogenic keratinocyte DNA damage-differentiation response to cell cycle stress. We now have studied this response to high or moderate single doses of UV irradiation. Whereas, as expected, high levels of UV induced p53-dependent apoptosis, moderate levels triggered squamous differentiation. UV-induced differentiation was not mediated by endogenous p53. Overexpression of the mitosis global regulator FOXM1 alleviated the proliferative loss caused by UV. Conversely, knocking-down the mitotic checkpoint protein Wee1 drove UV-induced differentiation into apoptosis. Therefore, the results indicate that mitosis checkpoints determine the response to UV irradiation. The differentiation response was also found in cells of head and neck epithelia thus uncovering a common regulation in squamous tissues upon chronic exposure to mutagens, with implications into homeostasis and disease.
Highlights
Stratified epithelia of the skin and head and neck are continuously exposed to mutagenic carcinogens
We have previously revealed a keratinocyte DNA damage-differentiation response (DDDR) to cell cycle deregulation or mitotic inhibition[11,12]
Since UV irradiation causes DNA damage and G2/M arrest[15,16,17], we have investigated whether sublethal levels trigger the differentiation-mitosis checkpoint (DMC)
Summary
Stratified epithelia of the skin and head and neck are continuously exposed to mutagenic carcinogens. Skin cancer in all forms (melanoma and carcinoma) has strikingly increased in the last decades due to social trends such as tanning or outdoor sports. It is well established that the main causes of epithelial skin cancer are continuous exposure to the genotoxic effect of ultraviolet (UV) and continuous cell renewal[1,2,3,4]. Skin sunburn has been found to trigger apoptosis of severely damaged keratinocytes in the epidermis[5,6]. Sublethal chronic UV irradiation impacts the keratinocyte genome even in the absence of burning and this is the main cause of precancerous mutations. Induction of massive apoptosis in the epidermis upon UV irradiation would compromise the skin function. The fate of moderately nonlethal UV-damaged keratinocytes and the mechanisms by which the epidermis avoids its precancerous potential are unclear
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