Corepressor

In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes.^[1] In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.

A corepressor

Function

Prokaryotes

In prokaryotes, the term corepressor is used to denote the activating ligand of a repressor protein. For example, the E. coli tryptophan repressor (TrpR) is only able to bind to DNA and repress transcription of the trp operon when its corepressor tryptophan is bound to it. TrpR in the absence of tryptophan is known as an aporepressor and is inactive in repressing gene transcription.^[2] Trp operon encodes enzymes responsible for the synthesis of tryptophan. Hence TrpR provides a negative feedback mechanism that regulates the biosynthesis of tryptophan.

In short tryptophan acts as a corepressor for its own biosynthesis.^[3]

Eukaryotes

In

In humans several dozen to several hundred corepressors are known, depending on the level of confidence with which the characterisation of a protein as a corepressors can be made.[7]

Examples of corepressors

NCoR

NCoR (nuclear receptor co-repressor) directly binds to the D and E domains of nuclear receptors and represses their transcriptional activity.^[8][9][10] Class I histone deacetylases are recruited by NCoR through SIN3, and NCoR directly binds to class II histone deacetylases.^[8][10][11]

Silencing mediator for retinoid and thyroid-hormone receptor

SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), also known as NCoR2, is an alternatively spliced SRC-1(steroid receptor coactivator-1).^[8][9] It is negatively and positively affected by MAPKKK (mitogen activated protein kinase kinase kinase) and casein kinase 2 phosphorylation, respectively.^[8] SMRT has two major mechanisms: first, similar to NCoR, SMRT also recruits class I histone deacetylases through SIN3 and directly binds to class II histone deacetylases.^[8] Second, it binds and sequesters components of the general transcriptional machinery, such as transcription factor II B.^[8][10]

Role in biological processes

Corepressors are known to regulate transcription through different activation and inactivation states.^[12][13]

NCoR and SMRT act as a corepressor complex to regulate transcription by becoming activated once the ligand is bound.^{[12][13][14][15]} Knockouts of NCoR resulted in embryo death, indicating its importance in erythrocytic, thymic, and neural system development.^[15][16]

Mutations in certain corepressors can result in deregulation of signals.^[13] SMRT contributes to cardiac muscle development, with knockouts of the complex resulting in less developed muscle and improper development.^[13]

NCoR has also been found to be an important checkpoint in processes such as inflammation and macrophage activation.^[15]

Recent evidence also suggests the role of corepressor RIP140 in metabolic regulation of energy homeostasis.^[14]

Clinical significance

Diseases

Since corepressors participate and regulate a vast range of gene expression, it is not surprising that aberrant corepressor activities can cause diseases.^[17]

Corepressors present many potential avenues for drugs to target a vast range of diseases.[22]

Activated liver X receptor (LXR) forms a complex with corepressors to suppress the inflammatory response in rheumatoid arthritis, making LXR agonists like GW3965 a potential therapeutic strategy.^[31][32] Ursodeoxycholic acid (UDCA), by upregulating the corepressor small heterodimer partner interacting leucine zipper protein (SMILE), inhibits the expression of IL-17, an inflammatory cytokine, and suppresses Th17 cells, both implicated in rheumatoid arthritis.^[33][34] This effect is dose-dependent in humans, and UCDA is thought to be another prospective agent of rheumatoid arthritis therapy.^[33]

See also

• Transcription coregulator
• TcoF-DB

References