Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
NUPEB & Biological Sciences Department, Federal University of Ouro Preto, Ouro Preto, MG, Brazil.
Free Radic Biol Med. 2019 Feb 1;131:432-442. doi: 10.1016/j.freeradbiomed.2018.12.012. Epub 2018 Dec 13.
The UVA component of sunlight induces DNA damage, which are basically responsible for skin cancer formation. Xeroderma Pigmentosum Variant (XP-V) patients are defective in the DNA polymerase pol eta that promotes translesion synthesis after sunlight-induced DNA damage, implying in a clinical phenotype of increased frequency of skin cancer. However, the role of UVA-light in the carcinogenesis of these patients is not completely understood. The goal of this work was to characterize UVA-induced DNA damage and the consequences to XP-V cells, compared to complemented cells. DNA damage were induced in both cells by UVA, but lesion removal was particularly affected in XP-V cells, possibly due to the oxidation of DNA repair proteins, as indicated by the increase of carbonylated proteins. Moreover, UVA irradiation promoted replication fork stalling and cell cycle arrest in the S-phase for XP-V cells. Interestingly, when cells were treated with the antioxidant N-acetylcysteine, all these deleterious effects were consistently reverted, revealing the role of oxidative stress in these processes. Together, these results strongly indicate the crucial role of oxidative stress in UVA-induced cytotoxicity and are of interest for the protection of XP-V patients.
阳光中的 UVA 成分会导致 DNA 损伤，而这些损伤基本上是皮肤癌形成的原因。色素性干皮病变异型（XP-V）患者的 DNA 聚合酶 pol eta 存在缺陷，这种酶能促进阳光诱导的 DNA 损伤后的跨损伤合成，这意味着他们的皮肤癌发病率增加。然而，UVA 光在这些患者的致癌作用尚不完全清楚。本研究的目的是比较 XP-V 细胞与经互补修复后的细胞，以确定 UVA 诱导的 DNA 损伤及其后果。两种细胞均能被 UVA 诱导产生 DNA 损伤，但 XP-V 细胞的损伤清除受到特别影响，这可能是由于 DNA 修复蛋白的氧化，这一点可通过羰基化蛋白的增加得到证实。此外，UVA 照射会导致 XP-V 细胞的复制叉停滞和 S 期细胞周期阻滞。有趣的是，当细胞用抗氧化剂 N-乙酰半胱氨酸处理时，所有这些有害影响都得到了一致的逆转，这表明氧化应激在这些过程中起作用。综上所述，这些结果强烈表明氧化应激在 UVA 诱导的细胞毒性中起着至关重要的作用，这对于 XP-V 患者的保护具有重要意义。
