Regulation of gene expression by the ubiquitin-proteasome system

Abstract

Transcription is the foremost regulatory point during the process of producing a functional protein. Not only specific genes need to be turned on and off according to growth and environmental conditions, the amounts and quality of transcripts produced are fine-tuned to offer optimal responses. As a result, numerous regulatory mechanisms converge to provide temporal and spatial specificity for this process. In the past decade, the ubiquitin-proteasome system (UPS), which is best known as a pathway for intracellular proteolysis, has emerged as another pivotal player in the control of gene expression. There is increasing evidence that the UPS has both proteolytic and non-proteolytic functions in multiple aspects of the transcription process, including initiation, elongation, mRNA processing as well as chromatin dynamics. In this review, we introduce the many interfaces between the UPS and transcription with focuses on the mechanistic understanding of UPS function in each process.

Fig. 1

(A) A schematic of different types of ubiquitin modifications and their functions. Ubiquitin has seven lysines and an N-terminal amine, each of which can engage in polyUb chain formation. These diverse modifications are associated with a large variety of biological functions, some of which are still poorly understood. (B) A schematic of the 26S proteasome and its subcomplexes.

Fig. 1

(A) A schematic of different types of ubiquitin modifications and their functions. Ubiquitin has seven lysines and an N-terminal amine, each of which can engage in polyUb chain formation. These diverse modifications are associated with a large variety of biological functions, some of which are still poorly understood. (B) A schematic of the 26S proteasome and its subcomplexes.

Fig. 2

The UPS regulates transcription via both proteolytic and non-proteolytic approaches. (A) Ubiquitylation and degradation of the activator facilitates promoter escape of RNA polymerase II in each round of transcription. AD, activation domain; DBD, DNA binding domain; UAS, upstream activating sequences; GTF, general transcription factor. (B) Mono-ubiquitylation of the activator facilitates transcription by preventing APIS from stripping the activator off DNA. (C) Interactions between the activator, proteasome and SAGA stabilize the ternary complex to facilitate transcription.

Fig. 2

The UPS regulates transcription via both proteolytic and non-proteolytic approaches. (A) Ubiquitylation and degradation of the activator facilitates promoter escape of RNA polymerase II in each round of transcription. AD, activation domain; DBD, DNA binding domain; UAS, upstream activating sequences; GTF, general transcription factor. (B) Mono-ubiquitylation of the activator facilitates transcription by preventing APIS from stripping the activator off DNA. (C) Interactions between the activator, proteasome and SAGA stabilize the ternary complex to facilitate transcription.

Fig. 2

The UPS regulates transcription via both proteolytic and non-proteolytic approaches. (A) Ubiquitylation and degradation of the activator facilitates promoter escape of RNA polymerase II in each round of transcription. AD, activation domain; DBD, DNA binding domain; UAS, upstream activating sequences; GTF, general transcription factor. (B) Mono-ubiquitylation of the activator facilitates transcription by preventing APIS from stripping the activator off DNA. (C) Interactions between the activator, proteasome and SAGA stabilize the ternary complex to facilitate transcription.

Fig. 3

The UPS regulates mRNA export in multiple ways. The SAGA complex, possibly recruited by the proteasome, can relocate the gene to the proximity of the NPC via the Sus1 subunit. Ubiquitylation of Hpr1 is coupled to transcription and facilitates recruitment of mRNA receptor Mex67. As part of the mRNA receptor complex, dissociation of Yra1 from mature transcript is dependent on mono-ubiquitylation.