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Signalling mechanisms and cellular functions of SUMO

Abstract

Sumoylation is an essential post-translational modification that is catalysed by a small number of modifying enzymes but regulates thousands of target proteins in a dynamic manner. Small ubiquitin-like modifiers (SUMOs) can be attached to target proteins as one or more monomers or in the form of polymers of different types. Non-covalent readers recognize SUMO-modified proteins via SUMO interaction motifs. SUMO simultaneously modifies groups of functionally related proteins to regulate predominantly nuclear processes, including gene expression, the DNA damage response, RNA processing, cell cycle progression and proteostasis. Recent progress has increased our understanding of the cellular and pathophysiological roles of SUMO modifications, extending their functions to the regulation of immunity, pluripotency and nuclear body assembly in response to oxidative stress, which partly occurs through the recently characterized mechanism of liquid–liquid phase separation. Such progress in understanding the roles and regulation of sumoylation opens new avenues for the targeting of SUMO to treat disease, and indeed the first drug blocking sumoylation is currently under investigation in clinical trials as a possible anticancer agent.

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Fig. 1: The sumoylation cycle.
Fig. 2: Functional group modification, protein clustering and phase separation.
Fig. 3: Post-translational modification crosstalk.
Fig. 4: Roles of SUMO in nuclear processes.
Fig. 5: SUMO in immunity and the maintenance of pluripotency.

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Acknowledgements

The author apologizes to researchers whose contributions were not cited here owing to space constraints. The author gratefully acknowledges the reviewers for their constructive criticism and F. Trulsson for assisting with Fig. 1b,c. Work in the author’s laboratory is supported by the European Research Council (ERC), the Netherlands Organization for Scientific Research (NWO) and the Dutch Cancer Society.

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Correspondence to Alfred C. O. Vertegaal.

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The author receives funding from Millennium-Takeda for research on the SUMO E1 inhibitor TAK981.

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Glossary

RAN

A GTPase involved in nucleocytoplasmic transport of proteins and RNAs.

Pluripotency

Ability of stem cells to differentiate into any cell type required to form an organism.

Liquid–liquid phase separation

(LLPS). Biophysical process of tightly interacting proteins enabling the formation of small cellular domains that are separated from their surrounding environment to enhance biochemical reactions.

Pseudogenes

Segments of DNA that resemble a gene but lack critical elements and are therefore not expressed.

ZNF451

E4 enzyme that generates small ubiquitin-like modifier (SUMO) polymers.

E4 elongase

Enzyme that generates small ubiquitin-like modifier (SUMO) polymers.

Nuclear bodies

Membraneless nuclear substructure, assembled by liquid–liquid phase separation.

SP-RING

Siz/PIAS-RING domain present in Siz/PIAS SUMO E3 ligases catalyzing sumoylation of target proteins. This domain is a hybrid between RING and U-box domains as it contains a single zinc coordination site.

Helicase

Motor protein that separates two hybridized nucleic acid strands.

PML nuclear bodies

Dynamic nuclear bodies that contain promyelocytic leukaemia protein (PML) as a marker. These small nuclear substructures are assembled by phase separation.

Top-down mass spectrometry

Mass spectrometry method for analysis of intact proteins.

DNA–protein crosslinks

(DPCs). Crosslinks between DNA and a protein that constitute a replication-blocking lesion.

Topoisomerase 2

(TOP2). Decatenating enzyme that adjusts the topology of DNA by producing a double-strand break in DNA to manage tangles and supercoils, and subsequently religating the broken DNA molecule.

N 6-Adenosine methyltransferase complex

An enzyme that methylates adenosine at the N6 position in eukaryotic mRNAs, forming N6-methyladenosine.

Chromosome congression

Alignment of chromosomes at the spindle equator, at equal distances from both spindle poles.

Retinoic acid

A derivative of vitamin A that regulates cell growth, cell differentiation and organogenesis.

Alternative lengthening of telomeres

(ALT). A process that enables cells to maintain telomere length independently of the enzyme telomerase.

Innate immunity

The first line of defence against invading pathogens, which contrasts with the adaptive immune system, which is the second line of defence.

Dendritic cells

Cells that present antigens to the adaptive immune system to stimulate acquired immunity.

Cancer stem cells

A subpopulation of cancer cells which are capable of self-renewal.

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Vertegaal, A.C.O. Signalling mechanisms and cellular functions of SUMO. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00500-y

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