SUMO targets the APC/C to regulate transition from metaphase to anaphase

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.

The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation

“…We also demonstrate that SENP6 depletion leads to a reduction in cell proliferation and mitotic problems that ultimately lead to cell death, implicating a clinical potential for a SENP6 inhibitor against highly proliferative cancer cells. The recently published SUMO E1 inhibitor also caused mitotic problems, especially the accumulation of anaphase bridges 64,65 . Combined this indicates that precise timing of SUMO conjugation and precise timing of SUMO deconjugation are both essential for proper mitotic progression.…”

“…Purification of His10-SUMO-trimer binding proteins was essentially performed as described before 64 . In brief, BL21 competent Escherichia coli cells (New England Biolabs, Cat#C2527I) were transformed with pHIS-TEV30a:His10-ΔN11-SUMO2-trimer.…”

P53 suppresses SENP3 phosphorylation to mediate G2 checkpoint

“…Yeast SUMOylation mutants showed a large budded phenotype and fail to properly degrade APC/C substrates Pds1 and Clb3, indicating an essential role for SUMOylation during the mitotic transition 36 . Recently, APC4, one subunit of APC/ C complex, has been identified to be SUMOylated during mitosis and is required for timely anaphase onset 37,38 . Proteomic studies have also identified SUMOylation sites on other subunits of the APC/C 39 .…”

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

“…Sumoylation also regulates ubiquitination enzymes in other cellular contexts. For example, sumoylation of a subunit of the APC ubiquitin E3 in mitosis was recently suggested to help activate the latter for timely anaphase onset (Eifler et al, 2018; Lee et al, 2018). Of note, SUMO and ubiquitin can also antagonize each other’s effects, sometimes via modification of the same site(s), as has been shown for DNA replication factor PCNA (Zilio et al, 2017).…”