Comparison of DNA damage responses following equimutagenic doses of UVA and UVB: A less effective cell cycle arrest with UVA may render UVA-induced pyrimidine dimers more mutagenic than UVB-induced ones

Abstract

Mechanisms of UVA-mutagenesis remain a matter of debate. Earlier described higher rates of mutation formation per pyrimidine dimer with UVA than with UVB and other evidence suggested that a non-pyrimidine dimer-type of DNA damage contributes more to UVA- than to UVB-mutagenesis. However, more recently published data on the spectra of UVA-induced mutations in primary human skin cells and in mice suggest that pyrimidine dimers are the most common type of DNA damage-inducing mutations not only with UVB, but also with UVA. As this rebuts a prominent role of non-dimer type of DNA damage in UVA-mutagenesis, we hypothesized that the higher mutation rate at UVA-induced pyrimidine dimers, as compared to UVB-induced ones, is caused by differences in the way UVA- and UVB-exposed cells process DNA damage. Therefore, we here compared cell cycle regulation, DNA repair, and apoptosis in primary human fibroblasts following UVB- and UVA-irradiation, using the same physiologic and roughly equimutagenic doses (100-300 J m(-2) UVB, 100-300 kJ m(-2) UVA) we have used previously for mutagenesis experiments with the same type of cells. ELISAs for the detection of pyrimidine dimers confirmed that much fewer dimers were formed with these doses of UVA, as compared to UVB. We found that cell cycle arrests (intra-S, G1/S, G2/M), mediated at least in part by activation of p53 and p95, are much more prominent and long-lasting with UVB than with UVA. In contrast, no prominent differences were found between UVA and UVB for other anti-mutagenic cellular responses (DNA repair, apoptosis). Our data suggest that less effective anti-mutagenic cellular responses, in particular different and shorter-lived cell cycle arrests, render pyrimidine dimers induced by UVA more mutagenic than pyrimidine dimers induced by UVB.

Characterisation of the p53-Mediated Cellular Responses Evoked in Primary Mouse Cells Following Exposure to Ultraviolet Radiation

“…Our observations are consistent with a recent study that showed that UVA was unable to induce Ser15 phosphorylation of p53 in primary human fibroblasts at equimutagenic doses to those at which UVB was able to induce a phosphorylation response [23]. Ser15 phosphorylation is one of a plethora of post-translational modifications that are associated with stabilisation and activation of p53.…”

Transfection of pseudouridine-modified mRNA encoding CPD-photolyase leads to repair of DNA damage in human keratinocytes: A new approach with future therapeutic potential

“…It is well established that UVB irradiation induces cell cycle arrest and inhibits cell proliferation, which is partly mediated by CPD photolesions [53, 54]. Removal of CPDs after photoreactivation of keratinocytes transfected with photolyase mRNA increased survival, confirming that CPDs are major contributors to cell death after UVB irradiation [22, 31, 55, 56] and demonstrating that CPD-photolyase mRNA transfection is an effective tool for photorepair.…”

Diversity of Biological Effects Induced by Longwave UVA Rays (UVA1) in Reconstructed Skin

“…Together with oxidative DNA damage such as 8 oxo-guanine, UVA1 induced DNA damage have been shown to be mutagenic in vitro and in vivo and UVA–induced pyrimidine dimers would be more mutagenic than those induced by UVB [12], [35]–[37]. Interestingly, UVA1 induced DNA mutations were also preferentially formed in the basal layer of human epidermis attesting a particular vulnerability of this epidermal layer, location of epidermal stem cells, proliferative keratinocytes and melanocytes [38], [39].…”

“…In humans, UVA1 exposure during phototherapy sessions leads to acute side effects including skin dryness, pruritus, polymorphic light eruptions and herpes simplex virus reactivation [10], [11]. A potential carcinogenic effect in humans can be strongly suspected since these wavelengths are able to induce DNA lesions and mutagenesis, and an increasing risk towards melanoma has also been associated with use of sunbeds [5], [12], [13]. In addition, UVA1 wavelength range, in contrast to UVA2, is highly immunosuppressive in human in vivo and is thought to be the largest contributor to immunosuppression resulting from incidental daily sun exposure [14], [15].…”