Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20.

Nature Chemical Biology
Katherine V RichesonRandall W King

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/CCdc20 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 p31comet 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.

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Citations

Jan 12, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Luciana MoscaGianni Colotti
Jan 8, 2021·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Sinjini SarkarVilas D Nasare
Apr 5, 2021·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Christine SongSeungBaek Lee
May 27, 2021·Nature Chemical Biology·Geng-Yuan Chen, Michael A Lampson
Aug 8, 2021·International Journal of Molecular Sciences·Scott C Schuyler, Hsin-Yu Chen

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Datasets Mentioned

BETA
MG132

Methods Mentioned

BETA
ubiquitination
fluorescence microscopy
fixed
immunoprecipitation
fluorescence imaging
fixed cell assay
transfection
PCR
thermal shift
size exclusion chromatography

Software Mentioned

Sequest
ReAdW
MetaMorph
metaXpress
MATLAB
Imaris
exe
ImageJ

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