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.
Highlights
Cellular responses to the disruption of mitosis include the induction of cell death by apoptosis, which normally prevents the propagation of chromosomal abnormalities that result from defects in mitotic spindle assembly
Kinetochores that are unattached to spindle microtubules signal through the Mps1-dependent generation of the mitotic checkpoint complex (MCC), which inhibits the Cdc20-dependent activation of the anaphase-promoting complex or cyclosome (APC/C), an E3 ligase that ubiquitinates key substrates and targets them for destruction by the proteasome (Pines, 2011; Sivakumar & Gorbsky, 2015)
Entry into interphase is generally associated with increased cell survival, probably due to a raised apoptotic threshold, cells that have been arrested for a prolonged period in mitosis can subsequently undergo cell cycle arrest or post-mitotic cell death (Bekier et al, 2009; Huang et al, 2009; Uetake & Sluder, 2010; Colin et al, 2015)
Summary
Cellular responses to the disruption of mitosis include the induction of cell death by apoptosis, which normally prevents the propagation of chromosomal abnormalities that result from defects in mitotic spindle assembly. The propensity of cells to undergo apoptosis correlates with the duration of mitosis (Bekier et al, 2009; Huang et al, 2009; Colin et al, 2015), which indicates a progressive increase in pro-apoptotic signalling until it reaches a threshold sufficient to initiate cell death. Entry into interphase is generally associated with increased cell survival, probably due to a raised apoptotic threshold, cells that have been arrested for a prolonged period in mitosis can subsequently undergo cell cycle arrest or post-mitotic cell death (Bekier et al, 2009; Huang et al, 2009; Uetake & Sluder, 2010; Colin et al, 2015)
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