Mitotic Phosphorylation of SENP3 Regulates De-SUMOylation of Chromosome-Associated Proteins and Chromosome Stability

Progression of mitotic cell cycle as well as 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 de-SUMOylation activity towards chromosome-associated proteins including Topoisomerase IIα (Topo IIα). Cyclin B-dependent kinases 1 (CDK1) and protein phosphatase 1α (PP1α) 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 de-SUMOylation activity on Topoisomerase IIα. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a non-phosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins as well as chromosome stability in mitosis.

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