Atypical APC/C-dependent degradation of Mcl-1 provides an apoptotic timer during mitotic arrest

Lindsey A. Allan, Agnieszka Skowyra, Katie I. Rogers, Désirée Zeller, Paul R. Clarke

Research output: Contribution to journalArticle

12 Citations (Scopus)
175 Downloads (Pure)

Abstract

The initiation of apoptosis in response to the disruption of mitosis provides surveillance against chromosome instability. Here, we show that proteolytic destruction of the key regulator Mcl-1 during an extended mitosis requires the anaphase-promoting complex or cyclosome (APC/C) and is independent of another ubiquitin E3 ligase, SCFFbw7 Using live-cell imaging, we show that the loss of Mcl-1 during mitosis is dependent on a D box motif found in other APC/C substrates, while an isoleucine-arginine (IR) C-terminal tail regulates the manner in which Mcl-1 engages with the APC/C, converting Mcl-1 from a Cdc20-dependent and checkpoint-controlled substrate to one that is degraded independently of checkpoint strength. This mechanism ensures a relatively slow but steady rate of Mcl-1 degradation during mitosis and avoids its catastrophic destruction when the mitotic checkpoint is satisfied, providing an apoptotic timer that can distinguish a prolonged mitotic delay from normal mitosis. Importantly, we also show that inhibition of Cdc20 promotes mitotic cell death more effectively than loss of APC/C activity through differential effects on Mcl-1 degradation, providing an improved strategy to kill cancer cells.

Original languageEnglish
Article numbere96831
Pages (from-to)1-15
Number of pages15
JournalThe EMBO Journal
Volume37
Issue number17
Early online date9 Jul 2018
DOIs
Publication statusPublished - 3 Sep 2018

Keywords

  • apoptosis
  • Mcl-1
  • mitosis
  • mitotic cell death
  • proteolysis

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