Both SCFs and APC/C belong to the so-called “CRL” superfamily, due to their catalytic cores containing both “ Cullin” and “ RING ligase” subunits. To understand mechanisms orchestrating temporal regulation of biological processes such as cell division, it is important to understand how E3 ligases ubiquitylate their substrates. APC/C also regulates progression through other sequential processes, including meiosis, differentiation, morphogenesis, and migration of various post-mitotic neuronal cell types (reviewed in ). The two major families of E3 ubiquitin ligases that coordinate cell division are SCFs (SKP1-CUL1-Fbox proteins), which were initially recognized for regulating interphase and are now known to control many stages of the cell cycle, and Anaphase-Promoting Complex/Cyclosome (APC/C), which regulates mitosis, the exit from mitosis, and G1 (reviewed in ). This is crucial for preventing errant recurrence of processes such as DNA replication or cytokinesis. Another role of ubiquitin-mediated proteolysis is the termination of proteins, including cyclins, when their tasks in the cell cycle are completed. As examples, anaphase is initiated when the cohesin complex that binds sister chromosomes is cleaved by separase upon ubiquitin-mediated degradation of the inhibitor securin, and the G1-S transition is regulated by activation of cyclin-dependent kinases upon degradation of inhibitors p21 and p27. Indeed, it is now widely appreciated that cell cycle transitions are temporally controlled when crucial regulatory enzymes are activated through ubiquitin-mediated proteolysis of their inhibitors. In the mid-1990s, numerous discoveries converged on a new paradigm that these events are ordered in part by the timely ubiquitin-mediated proteolysis of cell cycle proteins. The discrete steps involving biosynthesis of cellular macromolecules, chromosome and organelle duplication, and subsequent mitosis rely on biochemical reactions occurring in proper sequence. Progression through the cell cycle has captivated cell biologists for more than a century.
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