Anti-mitotic drugs such as Taxol chronically activate the spindle assembly checkpoint (SAC) by stabilising microtubules and causing prolonged mitotic arrest through activation of cyclin-dependent kinase 1 (Cdk1). Prolonged SAC activation then induces mitochondrial-mediated apoptotic cell death. Although this feedback mechanism is relatively well characterised, just how SAC activation initiates cell death has remained elusive. In this study, Rajnikant Patel and colleagues (Darweesh et al., 2021) propose that the primary signal coupling SAC activation to apoptotic cell death is the formation and delivery of the Bax–Cdk1 and Bak–Cdk1 complexes to the outer mitochondrial membrane (OMM). The authors use a proteomic screen to look for binding partners for the pro-apoptotic protein Bax during Taxol-induced cell death, identifying a complex comprising Bax, Bak and Cdk1. They show that activated Bax interacts directly with Cdk1 in vitro, and mediates co-translocation of Cdk1 to the OMM; this step is necessary for the phosphorylation of Bcl-2 and Bcl-xL and the induction of cell death. This is the first report to identify the Bax–Cdk1 (and Bak–Cdk1) signalling complex and demonstrate its function during SAC-induced cell death. These findings provide new insight into the mechanism that regulates the balance between cell division and cell death.
