Differential Roles of Rad18 and Chk2 in Genome Maintenance and Skin Carcinogenesis Following UV Exposure.
Differential Roles of Rad18 and Chk2 in Genome Maintenance and Skin Carcinogenesis Following UV Exposure.
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DOI：
10.1016/j.jid.2018.05.015
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发表时间：
2018-12
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通讯作者：
Y. Tanoue;T. Toyoda;Jinghua Sun;Md Kawsar Mustofa;Chie Tateishi;Shinya Endo;N. Motoyama;K. Araki;Di Wu;Y. Okuno;T. Tsukamoto;M. Takeya;H. Ihn;C. Vaziri;S. Tateishi
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作者：
Y. Tanoue;T. Toyoda;Jinghua Sun;Md Kawsar Mustofa;Chie Tateishi;Shinya Endo;N. Motoyama;K. Araki;Di Wu;Y. Okuno;T. Tsukamoto;M. Takeya;H. Ihn;C. Vaziri;S. Tateishi
DNA 聚合酶 Eta (Polη) 的缺陷会导致阳光敏感性和皮肤癌倾向障碍着色性干皮病变异。 Polη 功能对上游 E3 泛素连接酶 Rad18 的依赖程度存在争议，并且尚未使用小鼠模型进行研究。因此，我们测试了 Rad18 在紫外线诱导的皮肤肿瘤发生中的作用。由于 Rad18 缺陷会导致 Chk2 发出补偿性 DNA 损伤信号，因此我们还研究了 Rad18 和 Chk2 之间的体内遗传相互作用。Chk2–/–Rad18–/– 小鼠容易发生自发性淋巴瘤。与野生型 (WT) 动物相比，Chk2–/– 和 Chk2–/–Rad18–/– 小鼠均易于发生 UV-B 照射诱导的皮肤肿瘤发生，但出乎意料的是，Rad18–/– 小鼠并未重现 Polη 突变体的皮肤肿瘤倾向。与 WT 培养物相比，紫外线照射的 Rad18–/– 细胞更容易受到 G1/S 停滞和细胞凋亡的影响。 Chk2 缺陷减轻了紫外线诱导的 G1/S 期停滞和 WT 和 Rad18–/– 细胞的凋亡，但导致基因组不稳定性增加。综上所述，我们的结果表明，Polη 在经紫外线处理的皮肤中的肿瘤抑制作用与 Rad18 无关。我们还定义了 Chk2 在抑制体内紫外线诱导的皮肤癌发生中的作用。这项研究将 Chk2 功能障碍确定为阳光诱发的人类皮肤肿瘤发生的潜在危险因素。
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.Chk2–/–Rad18–/–mice were prone to spontaneous lymphomagenesis. BothChk2–/–andChk2–/–Rad18–/–mice were prone to UV-B irradiation-induced skin tumorigenesis when compared with wild-type (WT) animals, but unexpectedlyRad18–/–mice did not recapitulate the skin tumor propensity of Polη mutants. UV-irradiatedRad18–/–cells were more susceptible to G1/S arrest and apoptosis thanWTcultures. Chk2 deficiency alleviated both UV-induced G1/S phase arrest and apoptosis ofWTandRad18–/–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 identifiesChk2dysfunction as a potential risk factor for sunlight-induced skin tumorigenesis in humans.