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  • Recent studies have also uncovered additional roles


    Recent studies have also uncovered additional roles for E2 enzymes and E2~Ub conjugates in modulating the activity of deubiquitinating enzymes (DUBs), such as OTUB1 (Juang et al., 2012, Wiener et al., 2013, Wiener et al., 2012). Interestingly, OTUB1 has also been shown to associate and modulate the stability of cIAP1 (Goncharov et al., 2013). Together, these studies highlight the central role of E2~Ub conjugates in regulating cell death and it will be of considerable interest to understand the factors that influence the balance between E3-E2~Ub and DUB-E2~Ub interactions. We anticipate that biochemically defined assays that require preparations of pure reagents, such as those described here, will be essential for this understanding.
    CRL4 E3 ligases in tumorigenesis
    Small molecule-based PROTACs
    PROTAC: Major biological impacts
    Acknowledgements The authors sincerely apologize to all those colleagues whose important work was not cited in this paper owing to space limitations. They thank the members of Wei laboratory for critical reading and discussion of the manuscript. W.W. is a Leukemia & Lymphoma Society (LLS) research scholar. This work was supported in part by Scientific Research Training Program for Young Talents (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology) to J.C., by National Natural Science Foundation of China (81572413) to K.T., by the V Foundation for Cancer Research to P.Z., and by US National Institutes of Health (NIH) grants to P. Z. (CA159925 and CA213992) and W.W. (GM094777 and CA177910).
    Introduction Progression through the cell cycle has captivated cell biologists for more than a century. The discrete steps involving biosynthesis of cellular macromolecules, chromosome and organelle duplication, and subsequent mitosis rely on CEP-37440 mass occurring in proper sequence. In the mid-1990s, numerous discoveries converged on a new paradigm that these events are ordered in part by the timely Ub-mediated proteolysis of cell cycle proteins 1, 2. Indeed, it is now widely appreciated that cell cycle transitions are temporally controlled when crucial regulatory enzymes are activated through Ub-mediated proteolysis of their inhibitors. As examples, anaphase is initiated when the cohesin complex that binds sister chromosomes is cleaved by separase upon Ub-mediated degradation of the inhibitor securin, and the G1–S transition is regulated by activation of cyclin-dependent kinases (CDKs) upon degradation of inhibitors p21 and p27. Another role of Ub-mediated proteolysis is the termination of proteins, including cyclins, when their tasks in the cell cycle are completed. This is crucial for preventing errant recurrence of processes such as DNA replication or cytokinesis. The two major families of E3 ubiquitin ligases (see Glossary) 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 1, 2, 3, 4, 5, 6). APC/C also regulates sequential progression through other stepwise processes, including meiosis, differentiation, morphogenesis, and migration of various postmitotic neuronal cell types (reviewed in 7, 8, 9, 10). To understand mechanisms orchestrating temporal regulation of biological processes such as cell division, it is important to understand how E3 ligases ubiquitylate their substrates. Both SCFs and APC/C belong to the so-called cullin-RING ligase (CRL) superfamily, due to their catalytic cores containing both Cullin and RING ligase subunits. Common features of CRLs include: (i) substrate degron sequences are recruited to variable substrate-receptor subunits that associate interchangeably with a dynamic cullin–RING catalytic core; and (ii) a specific cullin–RING core recruits and activates a transient thioester-bonded complex between Ub and another enzyme (typically an E2), from which Ub is transferred to the remotely bound substrate (typically forming an isopeptide bond between the C terminus of Ub and a substrate lysine) 11, 12.