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

TY - JOUR

T1 - Atypical APC/C-dependent degradation of Mcl-1 provides an apoptotic timer during mitotic arrest

AU - Allan, Lindsey A.

AU - Skowyra, Agnieszka

AU - Rogers, Katie I.

AU - Zeller, Désirée

AU - Clarke, Paul R.

N1 - This work was funded by Cancer Research UK (C275/A13424) and Worldwide Cancer Research (formerly the Association for International Cancer Research; 12-0105).

PY - 2018/9/3

Y1 - 2018/9/3

N2 - 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.

AB - 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.

KW - apoptosis

KW - Mcl-1

KW - mitosis

KW - mitotic cell death

KW - proteolysis

U2 - 10.15252/embj.201796831

DO - 10.15252/embj.201796831

M3 - Article

C2 - 29987118

SN - 0261-4189

VL - 37

SP - 1

EP - 15

JO - The EMBO Journal

JF - The EMBO Journal

IS - 17

M1 - e96831

ER -