Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The Central Lab at Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Cancer Res. 2018 May 1;78(9):2171-2178. doi: 10.1158/0008-5472.CAN-17-2288. Epub 2018 Feb 8.
Progression of mitotic cell cycle and chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here, we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 deSUMOylation activity towards chromosome-associated proteins, including topoisomerase IIα (TopoIIα). Cyclin B-dependent kinases 1 and protein phosphatase 1α were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively. SENP3 phosphorylation decreased its interaction with TopoIIα, resulting in reduced SENP3 deSUMOylation activity on TopoIIα. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a nonphosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins and chromosome stability in mitosis. Phosphorylation of SENP3 regulates SUMOylation of chromosome-associated proteins to maintain genomic stability during mitosis. .
有丝分裂细胞周期的进展和染色体的浓缩和分离受翻译后蛋白质修饰的控制，如磷酸化和 SUMO 化。然而，SUMO 异肽酶（SENP）如何调节细胞有丝分裂过程在很大程度上是未知的。在这里，我们证明了有丝分裂期间 SENP3 的精确磷酸化抑制了 SENP3 对染色体相关蛋白（包括拓扑异构酶 IIα（TopoIIα））的去 SUMO 化活性。细胞周期蛋白 B 依赖性激酶 1 和蛋白磷酸酶 1α 分别被鉴定为控制有丝分裂 SENP3 磷酸化的激酶和磷酸酶。SENP3 磷酸化降低了其与 TopoIIα 的相互作用，导致 TopoIIα 上的 SENP3 去 SUMO 化活性降低。此外，我们观察到表达不可磷酸化 SENP3 突变体的细胞有丝分裂停滞、染色体不稳定性增加和促进肿瘤发生。这些数据表明，SENP3 磷酸化在调节有丝分裂中染色体相关蛋白的 SUMO 化和染色体稳定性方面起着至关重要的作用。SENP3 的磷酸化调节染色体相关蛋白的 SUMO 化，以在有丝分裂过程中维持基因组稳定性。
