Abstract
Signal transduction by small ubiquitin-like modifier (SUMO) regulates a myriad of nuclear processes. Here we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery results in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identify the anaphase-promoting complex/cyclosome (APC/C), a master regulator of metaphase to anaphase transition. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798. SUMOylation is crucial for accurate progression of cells through mitosis and increases APC/C ubiquitylation activity toward a subset of its targets, including the newly identified target KIF18B. Combined, our findings demonstrate the importance of SUMO signal transduction for genome integrity during mitotic progression and reveal how SUMO and ubiquitin cooperate to drive mitosis.
Highlights
Signal transduction by small ubiquitin-like modifier (SUMO) regulates a myriad of nuclear processes
To enhance our insight into the role of SUMOylation[24,25,26] during mitosis, we have produced HeLa cell lines stably harboring inducible knockdown constructs for both subunits of the SUMOactivating enzyme (SAE1 and SAE2). These cells were analyzed by live cell microscopy to monitor the amount of time needed for full mitotic progression from nuclear envelope breakdown (NEB) until the separation of the sister chromatids in anaphase (Fig. 1a)
We found that the posttranslational modifier SUMO is essential for proper mitotic progression and showed that, similar to mice[24], depletion of the SUMO conjugation machinery delayed progression from metaphase to anaphase in human cancer cells and led to severe chromosomal segregation defects (Fig. 1)
Summary
Signal transduction by small ubiquitin-like modifier (SUMO) regulates a myriad of nuclear processes. Cell cycle progression is exquisitely regulated by protein posttranslational modifications (PTMs) including phosphorylation and ubiquitylation[4]. The abundance of critical cell cycle components is regulated by the ubiquitin–proteasome system, with a dominant role for the ubiquitin E3 ligase anaphase-promoting complex/cyclosome (APC/C)[7,8]. Activity of the APC/C is tightly controlled by binding of inhibitors and activators, destabilization of its subunits, and PTMs, such as phosphorylation[10,11,12,13] Deregulation of these control mechanisms and altered activity of the APC/C can lead to severe mitotic defects and genome instabilities and has been associated with the development of various human cancer types[14,15,16,17,18]
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