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浙大揭示SIVA1在细胞应对紫外线诱导的DNA损伤的作用

时间:2016-12-10 09:10 浏览:

紫外线可以诱导Thymidine-Thymidine二聚体的产生,从而阻断DNA复制。为了应对紫外线诱导的DNA损伤,细胞启用跨损伤DNA合成(Translesion DNA synthesis, TLS)途径对受损的DNA进行复制。TLS利用特异的低保真性跨损伤dna聚合酶以损伤的DNA为模板进行复制,从而保证细胞的存活。 跨损伤DNA聚合酶Polh的突变会导致皮肤癌发生频率明显升高,进一步表明跨损伤DNA合成在细胞应对紫外线诱导的DNA损伤应答中起着重要作用。研究表明E3 泛素连接酶RAD18介导的PCNA单泛素化是招募跨损伤DNA聚合酶到DNA损伤位点进行TLS所必需。 黄俊课题组发现SIVA1可以作为一个接头蛋白,招募E3泛素连接酶RAD18到它的底物PCNA上进而促进PCNA单泛素化,保证细胞在紫外线诱导DNA损伤后能及时并有效地启用跨损伤DNA合成,帮助细胞应对紫外线诱导的DNA损伤。该研究结果于2014年6月23日发表于The Journal of Cell biology杂志,论文题目是“SIVA1 directs the E3 ubiquitin ligase RAD18 for PCNA monoubiquitination”。黄俊博士是本文通讯作者,博士研究生韩金花是本文第一作者。该工作也是 The Journal of Cell Biology 杂志这一期的特色文章。 原文摘要: SIVA1 directs the E3 ubiquitin ligase RAD18 for PCNA monoubiquitination Jinhua Han, Ting Liu, Michael S.Y. Huen, Lin Hu, ZhIQiu Chen andJun Huang Translesion DNA synthesis (TLS) is a universal DNA damage tolerance mechanism conserved from yeast to mammals. A key event in the regulation of TLS is the monoubiquitination of proliferating cell nuclear antigen (PCNA). Extensive evidence indicates that the RAD6–RAD18 ubiquitin-conjugating/ligase complex specifically monoubiquitinates PCNA and regulates TLS repair. However, the mechanism by which the RAD6–RAD18 complex is targeted to PCNA has remained elusive. In this study, we used an affinity purification approach to isolate the PCNA-containing complex and have identified SIVA1 as a critical regulator of PCNA monoubiquitination. We show that SIVA1 constitutively interacts with PCNA via a highly conserved PCNA-interacting peptide motif. Knockdown of SIVA1 compromised RAD18-dependent PCNA monoubiquitination and Polη focus formation, leading to elevated ultraviolet sensitivity and mutation. Furthermore, we demonstrate that SIVA1 interacts with RAD18 and serves as a molecular bridge between RAD18 and PCNA, thus targeting the E3 ligase activity of RAD18 onto PCNA. Collectively, our results provide evidence that the RAD18 E3 ligase requires an accessory protein for binding to its substrate PCNA. 作者:浙江大学 点击: