Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C-Cdc20

Richeson, Katherine V.; Bodrug, Tatyana; Sackton, Katharine L.; Yamaguchi, Masaya; Paulo, Joao A.; Gygi, Steven P.; Schulman, Brenda A.; Brown, Nicholas G.; King, Randall W.

doi:10.1038/s41589-020-0495-z

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Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C-Cdc20

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Schulman, Brenda A.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Richeson, K. V., Bodrug, T., Sackton, K. L., Yamaguchi, M., Paulo, J. A., Gygi, S. P., et al. (2020). Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C-Cdc20. Nature Chemical Biology, 16, 546-555. doi:10.1038/s41589-020-0495-z.

Cite as: https://hdl.handle.net/21.11116/0000-0005-FB95-8

Abstract

The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that initiates anaphase and mitotic exit. APC/C is activated by Cdc20 and inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin as a small molecule ligand of Cdc20 that inhibits APC/C-Cdc20 and prolongs mitosis. Here we find that apcin paradoxically shortens mitosis when SAC activity is high. These opposing effects of apcin arise from targeting of a common binding site in Cdc20 required for both substrate ubiquitination and MCC-dependent APC/C inhibition. Furthermore, we found that apcin cooperates with p31(comet) to relieve MCC-dependent inhibition of APC/C. Apcin therefore causes either net APC/C inhibition, prolonging mitosis when SAC activity is low, or net APC/C activation, shortening mitosis when SAC activity is high, demonstrating that a small molecule can produce opposing biological effects depending on regulatory context.