Key Points
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Reversible post-translational protein modification by small ubiquitin-like modifier (SUMO), sumoylation, is a crucial mechanism in the maintenance of genomic integrity, in the regulation of proper gene expression patterns and in numerous signal transduction pathways and is thus essential for cell and tissue homeostasis in all eukaryotes.
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Numerous protein complexes contain multiple sumoylated proteins, suggesting that sumoylation regulates not only the activity of individual substrates but that of entire functional complexes. Furthermore, in complex signalling pathways, sumoylation frequently targets multiple elements, in some cases antagonizing the activity of one element while promoting that of another within the same pathway.
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Various biotic and abiotic stresses substantially alter the level of global cellular sumoylation. Importantly, numerous human tumours display marked upregulation of SUMO pathway components. This 'SUMOness' of cancers may indeed be required by tumour cells to maintain the robustness of compromised or otherwise easily misregulated gene expression programmes and signalling pathways. Sumoylation would therefore contribute substantially to cancer cell survival and proliferation in a potentially hostile microenvironment.
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Although strong inhibition of global cellular sumoylation carries obvious risks for all cells, partial or temporary inhibition may be sufficient to expose certain tumour-specific vulnerabilities (for example, susceptibility to inducers of apoptosis and/or senescence) and therefore could provide a promising approach for future therapeutic intervention in some settings.
Abstract
Post-translational protein modification by small ubiquitin-like modifier (SUMO), termed sumoylation, is an important mechanism in cellular responses to stress and one that appears to be upregulated in many cancers. Here, we examine the role of sumoylation in tumorigenesis as a possibly necessary safeguard that protects the stability and functionality of otherwise easily misregulated gene expression programmes and signalling pathways of cancer cells.
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Acknowledgements
The authors apologize to the researchers whose contributions were not cited here owing to space constraints. The authors gratefully acknowledge the reviewers for their constructive criticisms and G. Fourel, J. Campbell, A. Krebs and the members of the Dejean Lab for valuable input. Work in the authors' laboratory is supported by grants from the European Research Council (ERC AdG-294341 'SUMOSTRESS'), the Institute National du Cancer (INCa), the Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisée) and Odyssey-RE (to A.D.).
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Glossary
- SUMO
-
Small protein belonging to the UBL (ubiquitin-like) family of proteins that are subject to enzyme-mediated covalent attachment to other proteins or chemical groups. Three functional paralogues exist in mammals, SUMO1, SUMO2 and SUMO3, of which the latter two (often called SUMO2/3) can form poly-SUMO chains in vivo.
- Acute promyelocytic leukaemia
-
(APL). Leukaemia characterized by chromosomal translocations producing oncogenic fusion proteins of the retinoic acid receptor-α (RARα) and promyelocytic leukaemia protein (PML; most cases), PLZF, NPM or NUMA (rare cases); associated with a differentiation block producing immature granulocytes (promyelocytes).
- PML nuclear bodies
-
Approximately one-micron-sized mammalian subnuclear structures containing sumoylated PML and SP100 as principal components, as well as numerous other, more transient proteins often implicated in regulating cellular stress responses such as genotoxic and oxidative stress.
- SUMO-targeted ubiquitin ligase
-
(StUbL). A ubiquitin E3 ligase containing SUMO-interacting motifs that binds SUMO-modified proteins to promote their degradation by the ubiquitin–proteasome system.
- SUMO E2 conjugating enzyme
-
The enzyme (usually called UBC9) that transfers SUMO to its substrate. In contrast to the ubiquitin E2, the SUMO E2 enzyme is unique in all organisms.
- SUMO1/sentrin specific peptidase
-
(SENP). SUMO-specific cysteine protease capable of removing mature SUMO from its substrate (isopeptidase activity) and/or from its carboxy-terminal extension (maturation endopeptidase activity). Mammals possess six SENPs (SENP1, SENP2, SENP3, SENP5, SENP6 and SENP7), as well as the unrelated DESI1, DESI2 and USPL1 SUMO proteases.
- SUMO E1 activating enzyme
-
In the SUMO system, the ATP-requiring, dimeric SAE1–SAE2 (also known as AOS1–UBA2) enzyme that makes the first high-energy thioester bond with mature SUMO that is necessary for the subsequent transfer steps.
- SUMO E3 ligase
-
The protein that brings the SUMO-charged E2 enzyme and substrate together. The canonical E3 ligases in mammals are the PIAS proteins (PIAS1–4) and MMS21 (also known as NSE2).
- Negatively charged amino acid-dependent sumoylation motif
-
A variant of the sumoylation consensus motif, ψKxE/D, (consisting of a bulky hydrophobic residue, ψ, the modified lysine, K, any amino acid, X, and an acidic residue, E or D) that contains additional negatively charged (for example, E or D) or phosphorylated (S, T or Y) residues further downstream.
- SUMO-interacting motif
-
A short peptide motif facilitating non-covalent interactions (generally weak) with SUMO. SUMO-targeted ubiquitin ligases usually contain several such motifs resulting in stronger interactions with poly- or multi-sumoylated substrates.
- Senescence-associated heterochromatin foci
-
Microscopically visible, dense nuclear structures with features of heterochromatin (for example, repressive histone marks) that are characteristic of some senescent cells.
- ChIP–seq
-
Chromatin immunoprecipitation and next-generation sequencing; a method used to determine genome-wide binding patterns of chromatin-associated proteins using specific antibodies.
- SUMO-regulated ubiquitin ligases
-
(SrUbLs). Directly sumoylated ubiquitin E3 ligases, such as RNF8, RNF168 or BRCA1, involved in DNA double-strand break repair.
- Synthetic lethal interactions
-
Occur when inhibition or mutation of one or the other of two given factors is viable but simultaneous inhibition is lethal. Non-oncogene addiction is considered a specific example of this concept.
- Pathogen-associated molecular patterns
-
(PAMPs). Pathogen-derived peptide, cell wall (for example, lipopolysaccharide) or nucleic acid fragments recognized by specific pattern recognition receptors (PRRs) that induce the innate immune response.
- Toll-like receptor
-
(TLR). Member of a family of pattern recognition receptors that bind pathogen-associated molecular patterns.
- Warburg effect
-
The metabolic shift, seen in many tumours, towards aerobic glycolysis that favours high anabolic rates and is compatible with, and inducible by, hypoxic conditions.
- Modules
-
Systems theory concept describing organization of functional elements, for example, in physical structures or metabolic pathways; usually viewed as contributing to the robustness of the entire system.
- Non-oncogene addiction
-
The concept that targeting certain stress tolerance or other non-oncogene pathways inhibits or kills cancer cells.
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Seeler, JS., Dejean, A. SUMO and the robustness of cancer. Nat Rev Cancer 17, 184–197 (2017). https://doi.org/10.1038/nrc.2016.143
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DOI: https://doi.org/10.1038/nrc.2016.143
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