Regulation of the cell cycle and centrosome biology by deubiquitylases

Abstract

Post-translational modification of proteins by ubiquitylation is increasingly recognised as a highly complex code that contributes to the regulation of diverse cellular processes. In humans, a family of almost 100 deubiquitylase enzymes (DUBs) are assigned to six subfamilies and many of these DUBs can remove ubiquitin from proteins to reverse signals. Roles for individual DUBs have been delineated within specific cellular processes, including many that are dysregulated in diseases, particularly cancer. As potentially druggable enzymes, disease-associated DUBs are of increasing interest as pharmaceutical targets. The biology, structure and regulation of DUBs have been extensively reviewed elsewhere, so here we focus specifically on roles of DUBs in regulating cell cycle processes in mammalian cells. Over a quarter of all DUBs, representing four different families, have been shown to play roles either in the unidirectional progression of the cell cycle through specific checkpoints, or in the DNA damage response and repair pathways. We catalogue these roles and discuss specific examples. Centrosomes are the major microtubule nucleating centres within a cell and play a key role in forming the bipolar mitotic spindle required to accurately divide genetic material between daughter cells during cell division. To enable this mitotic role, centrosomes undergo a complex replication cycle that is intimately linked to the cell division cycle. Here, we also catalogue and discuss DUBs that have been linked to centrosome replication or function, including centrosome clustering, a mitotic survival strategy unique to cancer cells with supernumerary centrosomes.

Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15

“…Monoubiquitin or polyubiquitin chains are appended to substrates by E1/E2/E3 ligases, and may subsequently be removed by deubiquitinases (DUBs) to reverse signals or stabilize proteins (Clague et al, 2013). As knowledge has accumulated regarding the structure, function, and biology of DUBs Heideker and Wertz, 2015), it has become apparent that each DUB plays a distinct role in the regulation of different components in cell biology and signaling (Darling et al, 2017;Kumari et al, 2017;Lim et al, 2016;Pinto-Fernandez and Kessler, 2016).…”

The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity

“…Monoubiquitin or polyubiquitin chains are appended to substrates by E1/E2/E3 ligases, and may subsequently be removed by a family of almost 100 deubiquitylases (DUBs) to reverse signals or stabilise proteins2,3. As specific substrates are gradually assigned to each DUB4–6, it is becoming apparent that many play roles in cell cycle progression and maintenance of genome integrity7–10. DUBs can be regulated by conformational changes, adaptor proteins or post-translational modifications, which control their activity or recruitment to specific complexes11,12.…”

With Age Comes Maturity: Biochemical and Structural Transformation of a Human Centriole in the Making

“…While novel centrosomal proteins are still being discovered, about 200 core centrosome proteins (systematized in a centrosome data base, [43,44]) have been identified through proteomic analyses [45][46][47][48]. The stoichiometry and intra-centrosomal localization of centrosomal components changes during the cell cycle and is dependent upon regulated transcription, degradation, and posttranslational modifications [49][50][51][52][53].…”