Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control

The covalent modification of proteins with ubiquitin is required for accurate cell division in all eukaryotes. Ubiquitylation depends on an enzymatic cascade, in which E3 enzymes recruit specific substrates for modification. Among similar to 600 human E3s, the SCF (Skp1-cullin1-F-box) and the APC/C (anaphase-promoting complex/cyclosome) are known for driving the degradation of cell cycle regulators to accomplish irreversible cell cycle transitions. The cell cycle machinery reciprocally regulates the SCF and APC/C through various mechanisms, including the modification of these E3s or the binding of specific inhibitors. Recent studies have provided new insight into the intricate relationship between ubiquitylation and the cell division apparatus as they revealed roles for atypical ubiquitin chains, new mechanisms of substrate and E3 regulation, as well as extensive crosstalk between ubiquitylation enzymes. Here, we review these emerging regulatory mechanisms of ubiquitin-dependent cell cycle control and discuss how their manipulation might provide therapeutic benefits in the future. This article is part of a Minifocus on Ubiquitin. For further reading, please see related articles: 'Ubiquitin and SUMO in DNA repair at a glance' by Helle D. Ulrich (J. Cell Sci. 125, 249-254). 'The role of ubiquitylation in receptor endocytosis and endosomal sorting' by Kaisa Haglund and Ivan Dikic (J. Cell Sci. 125, 265-275). 'Cellular functions of the DUBs' by Michael J. Clague et al. (J. Cell Sci. 125, 277-286). 'HECT and RING finger families of E3 ubiquitin ligases at a glance' by Meredith B. Metzger et al. (J. Cell Sci. 125, 531-537). 'Non-canonical ubiquitin-based signals for proteasomal degradation' by Yelena Kravtsova-Ivantsiv and Aaron Ciechanover (J. Cell Sci. 125, 539-548). 'No one can whistle a symphony alone how different ubiquitin linkages cooperate to orchestrate NF-kappa B activity' by Anna C. Schmukle and Henning Walczak (J. Cell Sci. 125, 549-559).