Cdc20: At the Crossroads between Chromosome Segregation and Mitotic Exit

Abstract

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.

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

“…1 Our findings may be relevant to the design of ad hoc therapeutic strategies that take advantage of aneuploid cell dependency on chaperone pathways, protein turnover, heightened metabolism, and a deregulated cell cycle. 50 CDC20 is also a promising target for anticancer therapies, 51 and preclinical data suggest that chemical inhibition of APC/C alone or in combination with topoisomerase poisons 52 or defective sister chromatid cohesion 53 may be explored as potential synthetic lethal strategies under the aneuploid condition. Novel biological insights into disease mechanisms, such as those obtained in our study, could boost the development of new personalized medicinebased trials.…”

“…Candidate strategies include a combination of microtubule depolymerizing drugs and PLK1 inhibitors, which drove BCL2 inactivation in a rhabdomyosarcoma model, 48 dual topoisomerase I and CHK1 inhibition, which achieved a curative response in the context of decreased expression of RAD50 in carcinoma, 49 and simultaneous targeting of glycolytic metabolism and Aurora kinases, which killed AML cells. 50 CDC20 is also a promising target for anticancer therapies, 51 and preclinical data suggest that chemical inhibition of APC/C alone or in combination with topoisomerase poisons 52 or defective sister chromatid cohesion 53 may be explored as potential synthetic lethal strategies under the aneuploid condition.…”

Identification of differentially expressed genes in hepatocellular carcinoma by integrated bioinformatic analysis

“…CDC20 encodes cell division cycle 20, which is a regulator of cell cycle checkpoints. It binds directly to another regulatory factor, Cdh1, and activates the late mitotic promoting complex APC, which plays an important role in late-stage of cell division and withdrawal from mitosis [33, 34]. Recently, an increasing number of studies have shown that CDC20 is a carcinogenic factor that is widely regulated in a variety of human malignancies, including lung cancer, kidney cancer and prostate cancer.…”

γ-H2AX is present at mouse meiotic kinetochores

“…The SAC regulates metaphase to anaphase transition preventing entry into anaphase until all sister kinetochores are attached to the microtubules from opposite spindle poles ensuring the fidelity of chromosome segregation (Lara-Gonzalez et al, 2012;Dou et al, 2019). Several SAC components such as MAD1, MAD2, MAD3/BUBR1, BUB1, and BUB3 are localized to unattached kinetochores and participate in a signaling network that leads the inhibition of the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) through recruiting CDC20, an activation factor of the APC/C (Kapanidou et al, 2017).…”