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How the ubiquitin–proteasome system controls transcription

Key Points

  • The ubiquitin–proteasome system regulates transcriptional control at many levels, and involves both proteolytic and non-proteolytic activities.

  • Histone ubiquitylation forms part of the 'histone code' that distinguishes transcriptionally active from inactive chromatin. In yeast, ubiquitylation of histone H2B has an important role in transcriptional gene silencing.

  • Ubiquitylation of RNA polymerase II is important for transcription-coupled DNA repair, in which the presence of DNA damage in a transcribed gene stops transcription and allows for the coordinated entry of the DNA-repair machinery.

  • Ubiquitin and ubiquitin-family members, including SUMO, control transcriptional activators by regulating their location (cytoplasmic versus nuclear, or in specific nuclear regions, for example, nuclear bodies), activity (for example, regulating the association of transcription factors with partner proteins) and abundance (by proteolysis).

  • The ability of transcriptional activators to engage the ubiquitin–proteasome system is tied intimately to their ability to activate transcription. This intimate connection is likely to have an important role in temporally limiting the ability of an activator to stimulate target-gene expression. In addition, components of the ubiquitin–proteasome system, most notably the proteasome itself, have a direct role in the regulation of gene expression.

  • The authors propose a model in which components of the ubiquitin–proteasome system converge on promoters to regulate the activity of numerous transcriptional components. First, ubiquitin-ligases are recruited to promoter complexes, where they ubiquitylate activators as well as RNA polymerase II and histones. Next, the 26S proteasome is recruited, which destroys activators and promotes transcription elongation, allowing transcription-coupled repair (if needed) as transcription proceeds. Eventually, the proteasome dissociates and RNA polymerase II returns to its initiation-competent form.

Abstract

Gene transcription and ubiquitin-mediated proteolysis are two processes that have seemingly nothing in common: transcription is the first step in the life of any protein and proteolysis the last. Despite the disparate nature of these processes, a growing body of evidence indicates that ubiquitin and the proteasome are intimately involved in gene control. Here, we discuss the deep mechanistic connections between transcription and the ubiquitin–proteasome system, and highlight how the intersection of these processes tightly controls expression of the genetic information.

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Figure 1: Control of chromatin by ubiquitin.
Figure 2: Regulation of TCR by ubiquitylation of RNA polymerase II.
Figure 3: Regulation of activators by the ubiquitin–proteasome system.
Figure 4: TADs and degrons overlap.
Figure 5: A unified model?

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Acknowledgements

We thanks Simone Salghetti for critical comments on the manuscript. W. P. T. is a Leukemia and Lymphoma Society of America Scholar. M. M. is a Marjorie H. Anderson Fellow. Work in W. P. T.'s laboratory is supported by a Cold Spring Harbor Laboratory Cancer Center Support Grant and by a US Public Health Service Grant from the National Cancer Institute.

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Correspondence to William P. Tansey.

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DATABASES

Saccharomyces Genome Database

ARG1

Def1

Med8

Swiss-Prot

β-catenin

Gal4

GSK-3β

histone deacetylase 6

Lef1

Met4

Met30

PIASγ

Rad6

Rad26

RLIM

Rsp5

SIR4

Spt23

Srb10

Sug1

Sug2

TAFII250

FURTHER INFORMATION

William P. Tansey's laboratory

Glossary

GENERAL TRANSCRIPTION FACTORS

A broadly expressed set of proteins that are generally required for accurate, promoter-initiated, transcription by RNA polymerase II.

UBIQUITIN

A highly-conserved 76-amino-acid protein that is linked covalently to lysine residues in other proteins and often signals their destruction.

PROTEASOME

A large, self-compartmentalized protease complex that destroys ubiquitylated substrates. The entire proteasome is often referred to as the 26S complex, which can be separated further into a 20S catalytic and a 19S regulatory complex.

UBIQUITYLATION

The process whereby ubiquitin is conjugated to a substrate protein. This is the chemically-appropriate terminology, as opposed to 'ubiquitination' and 'ubiquitinylation'.

UBIQUITIN-CONJUGATING ENZYME

(Ubc). The enzyme that is responsible for catalysing the transfer of ubiquitin to substrate proteins, and which might or might not be involved directly in substrate recognition.

TELOMERIC-GENE SILENCING

The transcriptional downregulation (silencing) of the expression of genes that are proximal to the telomere.

HISTONE CODE

The pattern of covalent modifications on core histones that functions as an epigenetic mark that distinguishes transcriptionally active regions from inactive regions of the genome.

DE-UBIQUITYLATION

The removal of ubiquitin by cleavage of the isopeptide bond that links ubiquitin to the substrate protein.

UBIQUITIN LIGASE

(Ub-ligase). A substrate recognition factor that brings a ubiquitin-conjugating enzyme and the substrate together. It is often a multiprotein complex.

TCR

(Transcription-coupled repair). The process by which transcriptionally active genes are preferentially repaired following DNA damage.

SUMO

(small ubiquitin-related modifier). One of a family of small ubiquitin-related proteins that are conjugated to substrates in a manner that is analogous to ubiquitylation.

TRANSCRIPTIONAL ACTIVATION DOMAIN

(TAD). A region in a transcription factor that interacts with the general transcriptional machinery to stimulate transcription.

DEGRON

(degradation signal). A specific element in a target protein that signals proteolysis. Usually the site of interaction with a ubiquitin ligase, but not necessarily the site of ubiquitin attachment.

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Muratani, M., Tansey, W. How the ubiquitin–proteasome system controls transcription. Nat Rev Mol Cell Biol 4, 192–201 (2003). https://doi.org/10.1038/nrm1049

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