Journal
EMBO JOURNAL
Volume 37, Issue 17, Pages -Publisher
WILEY
DOI: 10.15252/embj.201796831
Keywords
apoptosis; mitosis; Mcl-1; mitotic cell death; proteolysis
Categories
Funding
- Cancer Research UK [C275/A13424]
- Worldwide Cancer Research [12-0105]
- Biotechnology and Biological Sciences Research Council (BBSRC) EastBio Programme Studentship
- Cancer Research UK [13424] Funding Source: researchfish
- Worldwide Cancer Research [12-0105] Funding Source: researchfish
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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.
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