Trends in Biochemical Sciences
ReviewSUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer
Section snippets
SUMO: A Ubiquitin-like Modifier that Regulates Nuclear Processes
The complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of post-translational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications, such as phosphorylation [1], glycosylation [2], and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the
Twenty Years of SUMO Research in Cell Cycle Control
SUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO-conjugating enzyme Ubc9 was first proposed to be a ubiquitin-conjugating enzyme. Ubc9 was shown to be required for progression through mitosis by degrading M-phase cyclins [12]. Consequently, disrupting UBC9 in budding yeast resulted in large budded cells bearing only a single nucleus with a short spindle and replicated DNA, a hallmark of G2-M arrested
Redistribution of the SUMO Machinery during Mitosis
SUMO localizes at centromeres, kinetochores, and mitotic and meiotic chromosomes in different organisms, including humans and frogs 24, 25, 26. In Caenorhabditis elegans, SUMO accumulates at the metaphase plate, but its presence decreases during anaphase [27], which is regulated via the interplay between the SUMO ligase gamete-expressed 3 (GEX3)-interacting protein 17 (GEI-17) and the SUMO protease Ubiquitin-Like Protease 4 (ULP-4). These observations demonstrate that SUMO target proteins that
SUMOylation and Cyclin-Dependent Kinases in Concert
The activity and localization of the SUMO machinery can be influenced by interaction partners and by crosstalk with other post-translational modifications. Interestingly, SENP3 is heavily phosphorylated during mitosis, suggesting its regulation via mitotic kinases [42]. Additionally, kinases that are active at defined moments during cell cycle progression can also influence SUMOylation by cooperating with Ubc9. A subset of SUMO targets is regulated via an internal phosphorylation-dependent
Protein Group Modification at Mitotic Chromosomes
In many cases, several subunits of the same regulatory complexes are targeted via SUMOylation. This is consistent with proteomic studies showing that SUMO frequently modifies entire functional groups of proteins [56]. Protein group SUMOylation, potentially enhanced by the formation of longer SUMO2/3 chains on the target proteins, can trigger the formation of complexes at centromeric regions and, therefore, might be essential for chromosome alignment and segregation. Interestingly, both SENP6, a
Deregulation of the SUMO Machinery in Cancer Cells
Related to the essential role of SUMOylation in maintaining chromosome integrity and regulating cell proliferation, evidence is accumulating for a key role of SUMOylation in cancer. Many components of the SUMO machinery are highly expressed in cancer tissues, suggesting that activated SUMOylation is linked to tumor growth (Table 1). Overexpression of the SUMO-conjugating enzyme Ubc9 occurs in many types of cancer, including ovarian [63], colon, and prostate cancer [64], and promotes cell
Targeting the SUMO System
As described above, many components of the SUMO machinery are overexpressed in cancer tissues and knockdown of the SUMO pathway blocks cell proliferation and induces apoptosis. Therefore, is of interest to develop compounds that specifically block the activity of the SUMOylation machinery. Drugs targeting the SUMO-activating enzyme are currently under investigation. Chemical inhibitors, such as ginkgolic acid and anacardic acid, bind to the SUMO-activating enzyme and block the E1-SUMO
Concluding Remarks and Future Perspectives
Precisely timed post-translational modifications are essential to ensure accurate progression through the cell cycle. We now know extensive sets of ubiquitylation and phosphorylation events that are important for the transition from one cell cycle phase to the next. By contrast, we are limited in our understanding of SUMOylation events during cell cycle progression. Interestingly, inhibition of the SUMO pathway leads to cell cycle arrest in yeast and to decreased cell cycle progression and
Acknowledgments
The laboratory of A.C.O.V. is supported by the European Research Council (ERC) and the Netherlands Organisation for Scientific Research (NWO).
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2023, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :SUMOylation regulates target proteins involved in transcription, DNA repair, chromatin remodeling, pre-mRNA splicing, and ribosome assembly [123,124]. Protein SUMOylation can be stimulated by various cellular stresses [124] and is crucial for cell cycle progression [125]. However, the function of RBM39 SUMOylation remains elusive.