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[Ultraviolet A-induced DNA damage: role in skin cancer].

Authors
  • Beani, Jean-Claude
Type
Published Article
Journal
Bulletin de l'Académie nationale de médecine
Publication Date
Feb 01, 2014
Volume
198
Issue
2
Pages
273–295
Identifiers
PMID: 26263704
Source
Medline
License
Unknown

Abstract

Skin cancer is the most common human malignancy, and sunlight exposure is known to play a role in its genesis. Ultraviolet B (UVB) (300-320 nm) has long been considered responsible for the skin damage underlying these cancers, whereas the toxicity of UVA (320-400 nm) has been largely overlooked The intimate mechanisms of photocarcinogenicity remain poorly understood, but UV-induced DNA damage appears to be a major initiating event. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) photoproducts (6-4PPs) are the main dimeric lesions induced by UVB, whereas the genotoxic effects of UVA have long been attributed to oxidative damage, the main lesion being the oxidized base 8-oxo-7,8dihydroguanine (8-oxoGua). However; powerful new techniques for analyzing DNA damage (the Comet assay, and especially HPLC-MSIMS) have demonstrated that UVA irradiation mainly triggers the formation of CPDs, especially CPD-TT both in cell models and in total human skin. A direct photochemical process is currently thought to account for CPD induction by UVA. The multilayer structure of the epidermis protects against UVB-induced dipyrimidine lesions in total skin but offers only weak protection against UVA. In addition, repair efficiency is undermined by UVA. CPDs, the main DNA lesions induced by UVA in total skin (which is more permeable to UVA), are inefficiently repaired CPDs have strong mutagenic potential, and recent studies clearly show that CPDs, rather than 8-Oxo-Gua, are the main mutagenic photoproducts induced by UVA. The UV signature of induced mutations is characterized by transitions from C to T or CC to TT in dipyrimidine sequences. These mutations target the p53, patched 1 and SMO genes in carcinomas, and the PTEN RAC1, PPP6C, STK19 and PPP6C genes in melanomas of exposed skin. UVA also mainly induces CPDs in melanocytes, in amounts similar to those observed in keratinocytes, demonstrating that melanin does not prevent CPD formation. In contrast, UVA induces far more abundant 8-oxo-Gua production in melanocytes than in keratinocytes. Thus, under UVA irradiation, oxidative stress contributes more to DNA damage in melanocytes than in keratinocytes. In addition, baseline oxidative damage (in the absence of UVA) is already higher in melanocytes. The photosensitizer may be melanin itself. This is supported by a recent study based on a murine model, in which melanoma induction was shown to require both UVA and the presence of melanin in melanocytes, and is associated with oxidative damage to DNA. Conversely, UVB was found to initiate melanoma through a direct, pigment-independent pathway. Thus, two wavelength-dependent pathways can induce melanoma, with melanin playing an unexpected role. Constitutive pigmentation is very effective in preventing UV-induced damage, and a clear correlation can thus be found between, on the one hand, the amount of CPD TT produced by both UVB and UVA and, on the other hand, the minimum erythematous dose and the phototype. Melanin is thus a two-facetted molecule, protecting the skin when its synthesis is complete and when melanosomes take on their nucleus-protective geometric configuration in keratinocytes, but having a pro-oxidant action when only partially polymerized and exposed to UV Repeated exposure of volunteer skin shows that a tan induced by UVB provides little protection against DNA damage caused by subsequent exposure, while tanning with UVA provides no protection at all. Yet both UVB and UVA provoke DNA damage. All these recent data highlight the potential role of UVA in skin carcinogenesis, and reinforce epidemiological studies showing an increased risk of melanoma among users of tanning lamps, particularly young women. The decision by the International Agency for Research on Cancer to classify UVA and tanning devices as group 1 carcinogens, and the opinion issued by the French National Academy of Medicine on tanning booths, therefore appear to be fully justified. The use of tanning salons should be permanently banned

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