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

  • Nat Chem Biol. 2020 May;16(5):546-555. doi: 10.1038/s41589-020-0495-z.
Katherine V Richeson  1 ,  Tatyana Bodrug  2 ,  Katharine L Sackton  1 ,  Masaya Yamaguchi  3 ,  Joao A Paulo  1 ,  Steven P Gygi  1 ,  Brenda A Schulman  3  4 ,  Nicholas G Brown  5 ,  Randall W King  6
Affiliations
  • 1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 3. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4. Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 5. Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 6. Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 32152539 DOI: 10.1038/s41589-020-0495-z
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.

Products