Zheng Nana, Dai Xiangpeng, Wang Zhiwei, Wei Wenyi
a The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University , Suzhou , P. R. China.
b Department of Pathology , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.
Cell Cycle. 2016 Nov 16;15(22):3042-3047. doi: 10.1080/15384101.2016.1234552. Epub 2016 Sep 20.
Set8 is critically involved in transcription regulation, cell cycle progression and genomic stability. Emerging evidence has revealed that E3 ubiquitin ligases such as CRL4 and SCF regulate Set8 protein abundance. However, it is unclear whether other E3 ligase(s) could govern Set8 level for proper cell cycle progression in response to genotoxic stress such as UV irradiation. Recently, we report that the SCF complex regulates Set8 protein stability by targeting it for ubiquitination and subsequent degradation. Notably, Set8 interacts with the SCF E3 ligase complex. We further revealed a critical role of CKI in SCF-mediated degradation of Set8. Mechanistically, CKI-mediated phosphorylation of Set8 at the S253 site promotes its destruction by SCF. Importantly, SCF-dependent Set8 destruction also contributes to the tight control of cell proliferation and cell cycle progression, in response to UV irradiation. Here, we summarize our new findings regarding the crucial role of β-TRCP in CKI-mediated Set8 degradation, which could provide new evidence to support that dysregulation of a tight regulatory network of Set8 could lead to aberrant cell cycle process.
Set8在转录调控、细胞周期进程和基因组稳定性中起着关键作用。新出现的证据表明，诸如CRL4和SCF等E3泛素连接酶调节Set8蛋白丰度。然而，尚不清楚其他E3连接酶是否能够在响应紫外线照射等基因毒性应激时调控Set8水平以实现正常的细胞周期进程。最近，我们报道SCF复合物通过将Set8靶向泛素化并随后降解来调节其蛋白稳定性。值得注意的是，Set8与SCF E3连接酶复合物相互作用。我们进一步揭示了CKI在SCF介导的Set8降解中的关键作用。从机制上讲，CKI介导的Set8在S253位点的磷酸化促进了其被SCF的破坏。重要的是，响应紫外线照射时，SCF依赖的Set8破坏也有助于严格控制细胞增殖和细胞周期进程。在此，我们总结了关于β-TRCP在CKI介导的Set8降解中的关键作用的新发现，这可能为支持Set8紧密调控网络失调会导致异常细胞周期进程提供新证据。
