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

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

SUBMITTER: Richeson KV 

PROVIDER: S-EPMC7289404 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature