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 language | English |
---|---|
Article number | e96831 |
Pages (from-to) | 1-15 |
Number of pages | 15 |
Journal | The EMBO Journal |
Volume | 37 |
Issue number | 17 |
Early online date | 9 Jul 2018 |
DOIs | |
Publication status | Published - 3 Sept 2018 |
Keywords
- apoptosis
- Mcl-1
- mitosis
- mitotic cell death
- proteolysis
ASJC Scopus subject areas
- General Neuroscience
- Molecular Biology
- General Biochemistry,Genetics and Molecular Biology
- General Immunology and Microbiology