Cdc20: At the Crossroads between Chromosome Segregation and Mitotic Exit

Phosphorylation and dephosphorylation cascades acting on cell-division cycle protein 20 homologue (Cdc20) control cell division and genome stability. Various pools of Cdc20 complexes exist in the cell and undergo dynamic remodelling. Cdc20 is abnormally expressed in a wide range of tumours. Cdc20 constitutes a potential novel target for the treatment of cancer. The combination of traditional structural biology approaches with emerging technologies such as single-particle methods and high-resolution cryo-electron microscopy has enabled us to learn new details of Cdc20 functions in health and disease. These technological advances have facilitated a mechanistic understanding of Cdc20-dependent allosteric regulation of the anaphase-promoting complex or cyclosome (APC/C) at an unprecedented level of detail. Cell-division cycle protein 20 homologue (Cdc20) has important functions in chromosome segregation and mitotic exit. Cdc20 is the target of the spindle assembly checkpoint (SAC) and a key cofactor of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase, thus regulating APC/C ubiquitin activity on specific substrates for their subsequent degradation by the proteasome. Here we discuss the roles of Cdc20 in SAC signalling and mitotic exit, describe how the integration of traditional approaches with emerging technologies has revealed new details of Cdc20 functions, comment about the potential of Cdc20 as a therapeutic target for the treatment of human malignancies, and discuss recent advances and controversies in the mechanistic understanding of the control of chromosome segregation during cell division. Cell-division cycle protein 20 homologue (Cdc20) has important functions in chromosome segregation and mitotic exit. Cdc20 is the target of the spindle assembly checkpoint (SAC) and a key cofactor of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase, thus regulating APC/C ubiquitin activity on specific substrates for their subsequent degradation by the proteasome. Here we discuss the roles of Cdc20 in SAC signalling and mitotic exit, describe how the integration of traditional approaches with emerging technologies has revealed new details of Cdc20 functions, comment about the potential of Cdc20 as a therapeutic target for the treatment of human malignancies, and discuss recent advances and controversies in the mechanistic understanding of the control of chromosome segregation during cell division. a prevalent form of genetic instability observed in many types of human cancer. Aneuploidy is a condition in which premature separation of sister chromatids results in the loss or gain of chromosomes in daughter cells. a key concept in drug discovery that refers to the ensemble of all possible chemical compounds adhering to a given set of construction principles and boundary conditions to be considered in the search for new drugs. a specific protein degradation signal that is required for the regulated destruction of the protein degradation rate. A degron can be a short amino acid sequence or a structural motif. Some central components of the SAC, including Cdc20, contain multiple degrons. functions as an adaptor for the recruitment of other proteins. Proteins containing this domain are involved in SAC and meiotic checkpoint signalling and in the regulation of meiotic recombination. from the Greek kinētikos, ‘of motion’, and chōros, ‘place’ refers to the site for attachment of chromosomes to the microtubule spindle fibers that pull sister chromatids apart during mitosis and meiosis. a computerised image-processing technique where projection images of individual macromolecular complexes (a.k.a. particles) from cryo-EM samples are sorted to build a 3D reconstruction of the complexes, often with near-atomic resolution. an evolutionarily conserved safety device of eukaryotic organisms that ensures the fidelity of chromosome segregation on cell division. During mitosis or meiosis, the SAC prevents anaphase onset until all chromosomes are properly attached to spindle microtubules. the most widely used system to describe the stage of a cancer originating from a solid tumour. Most hospitals and medical centres use the TNM system as their main method for cancer reporting. ‘T’ refers to the size and extent of the main (usually referred to as the primary) tumour, ‘N’ to the number of nearby lymph nodes that have cancer, and ‘M’ to whether the cancer has metastasised (i.e., spread from the primary tumour to other parts of the body).