UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin
UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin
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DOI：
10.1038/jid.2008.61
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发表时间：
2008-09-01
影响因子：
6.5
通讯作者：
Ono, Tetsuya
中科院分区：
文献类型：
--
作者：
Ikehata, Hironbu;Kawai, Kazuaki;Ono, Tetsuya
UVA1诱导细胞基因组中8-羟基-2‘-脱氧鸟苷(8-OH-DGS)和环丁烷嘧啶二聚体(CPDS)的形成。然而，每种类型的损伤对UVA1体内遗传毒性的相对贡献尚不清楚。我们用364 nm的UVA1激光照射活体小鼠皮肤，分析了表皮和真皮中DNA损伤的形成和突变诱导。虽然观察到8-OH-DG和CPD的剂量依赖性增加，但根据皮肤基因组中诱导的突变谱：双嘧啶位置的C-T转变占主导地位，皮肤中的突变诱导特别是CPD的形成。此外，这些紫外线特异性突变优先发生在5‘-TCG-3’序列上，这表明CpG甲基化和光敏化介导的三联体能量转移是CPD介导的UVA1遗传毒性的原因。因此，正是CPD的形成，而不是氧化应激，有效地导致了UVA1暴露后正常皮肤的遗传毒性。我们还发现表皮和真皮对UVA1基因毒性的反应不同：UVA1照射后的突变诱导在所检测的所有光照水平的真皮中都受到抑制，而在一定的高光照度下，真皮中的突变诱导则趋于平稳。
UVA1 induces the formation of 8-hydroxy-2'-deoxyguanosines (8-OH-dGs) and cyclobutane pyrimidine dimers (CPDs) in the cellular genome. However, the relative contribution of each type of damage to the in vivo genotoxicity of UVA1 has not been clarified. We irradiated living mouse skin with 364-nm UVA1 laser light and analyzed the DNA damage formation and mutation induction in the epidermis and dermis. Although dose-dependent increases were observed for both 8-OH-dG and CPD, the mutation induction in the skin was found to result specifically from the CPD formation, based on the induced mutation spectra in the skin genome: the dominance of C-T transition at a dipyrimidine site. Moreover, these UV-specific mutations occurred preferentially at the 5'-TCG-3' sequence, suggesting that CpG methylation and photosensitization-mediated triplet energy transfer to thymine contribute to the CPD-mediated UVA1 genotoxicity. Thus, it is the CPD formation, not the oxidative stress, that effectively brings about the genotoxicity in normal skin after UVA1 exposure. We also found differences in the responses to the UVA1 genotoxicity between the epidermis and the dermis: the mutation induction after UVA1 irradiation was suppressed in the dermis at all levels of irradiance examined, whereas it leveled off from a certain high irradiance in the epidermis.