Department of Cell Maintenance, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.
Division of Pathology, National institute of Health Sciences Biological safety center, Tokyo, Japan.
J Invest Dermatol. 2018 Dec;138(12):2550-2557. doi: 10.1016/j.jid.2018.05.015. Epub 2018 May 31.
Defects in DNA polymerase Eta (Polη) cause the sunlight-sensitivity and skin cancer-propensity disorder xeroderma pigmentosum variant. The extent to which Polη function depends on the upstream E3 ubiquitin ligase Rad18 is controversial and has not been investigated using mouse models. Therefore, we tested the role of Rad18 in UV-inducible skin tumorigenesis. Because Rad18 deficiency leads to compensatory DNA damage signaling by Chk2, we also investigated genetic interactions between Rad18 and Chk2 in vivo. Chk2Rad18 mice were prone to spontaneous lymphomagenesis. Both Chk2 and Chk2Rad18 mice were prone to UV-B irradiation-induced skin tumorigenesis when compared with wild-type (WT) animals, but unexpectedly Rad18 mice did not recapitulate the skin tumor propensity of Polη mutants. UV-irradiated Rad18 cells were more susceptible to G1/S arrest and apoptosis than WT cultures. Chk2 deficiency alleviated both UV-induced G1/S phase arrest and apoptosis of WT and Rad18 cells, but led to increased genomic instability. Taken together, our results demonstrate that the tumor-suppressive role of Polη in UV-treated skin is Rad18 independent. We also define a role for Chk2 in suppressing UV-induced skin carcinogenesis in vivo. This study identifies Chk2 dysfunction as a potential risk factor for sunlight-induced skin tumorigenesis in humans.
DNA 聚合酶 Eta（Polη）缺陷导致对阳光敏感和皮肤癌倾向的疾病着色性干皮病变异型。Polη 功能在多大程度上依赖于上游 E3 泛素连接酶 Rad18 存在争议，并且尚未使用小鼠模型进行研究。因此，我们测试了 Rad18 在 UV 诱导的皮肤肿瘤发生中的作用。由于 Rad18 缺乏会导致 Chk2 的代偿性 DNA 损伤信号，因此我们还研究了 Rad18 和 Chk2 之间在体内的遗传相互作用。Chk2Rad18 小鼠容易自发发生淋巴瘤。与野生型（WT）动物相比，Chk2 和 Chk2Rad18 小鼠均容易发生 UV-B 照射诱导的皮肤肿瘤发生，但出人意料的是，Rad18 小鼠并没有重现 Polη 突变体的皮肤肿瘤倾向。与 WT 培养物相比，UV 照射的 Rad18 细胞更容易发生 G1/S 期阻滞和凋亡。Chk2 缺失减轻了 WT 和 Rad18 细胞的 UV 诱导的 G1/S 期阻滞和凋亡，但导致基因组不稳定性增加。总之，我们的结果表明，Polη 在 UV 处理的皮肤中的肿瘤抑制作用不依赖于 Rad18。我们还定义了 Chk2 在体内抑制 UV 诱导的皮肤致癌作用中的作用。这项研究确定了 Chk2 功能障碍是人类阳光诱导皮肤肿瘤发生的潜在危险因素。
