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Ubiquitylation is a reversible post-translational modification that has emerged as a key regulator of most complex cellular processes. It may rival phosphorylation in scope and exceed it in complexity. The dynamic nature of ubiquitylation events is important for governing protein stability, maintaining ubiquitin homeostasis and controlling ubiquitin-dependent signalling pathways. The human genome encodes ~80 active deubiquitylating enzymes (DUBs, also referred to as deubiquitinases), which exhibit distinct specificity profiles towards the various ubiquitin chain topologies. As a result of their ability to reverse ubiquitylation, these enzymes control a broad range of key cellular processes. In this Commentary we discuss the cellular functions of DUBs, such as their role in governing membrane traffic and protein quality control. We highlight two key signalling pathways – the Wnt and transforming growth factor β (TGF-β) pathways, for which dynamic ubiquitylation has emerged as a key regulator. We also discuss the roles of DUBs in the nucleus, where they govern transcriptional activity and DNA repair pathways.


  • 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). ‘Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control’ by Annamaria Mocciaro and Michael Rape (J. Cell Sci. 125, 255-263). ‘The role of ubiquitylation in receptor endocytosis and endosomal sorting’ by Kaisa Haglund and Ivan Dikic (J. Cell Sci. 125, 265-275). ‘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-κB activity’ by Anna C. Schmukle and Henning Walczak (J. Cell Sci. 125, 549-559).

  • Funding

    S.U. is a Cancer Research UK Senior Research Fellow (C20535/A6999).

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