Corepressor

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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.

Contents

A corepressor downregulates (or represses) the expression of genes by binding to and activating a repressor transcription factor. The repressor in turn binds to a gene's operator sequence (segment of DNA to which a transcription factor binds to regulate gene expression), thereby blocking transcription of that gene.

Corepressor Transcription Factor Complex on Regulatory Element Purple Corepressor Transcription Factor Complex on DNA.png
Corepressor Transcription Factor Complex on Regulatory Element

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 eukaryotes, a corepressor is a protein that binds to transcription factors. [4] In the absence of corepressors and in the presence of coactivators, transcription factors upregulate gene expression. Coactivators and corepressors compete for the same binding sites on transcription factors. A second mechanism by which corepressors may repress transcriptional initiation when bound to transcription factor/DNA complexes is by recruiting histone deacetylases which catalyze the removal of acetyl groups from lysine residues. This increases the positive charge on histones which strengthens the electrostatic attraction between the positively charged histones and negatively charged DNA, making the DNA less accessible for transcription. [5] [6]

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]

Acute myeloid leukemia (AML) is a highly lethal blood cancer characterized by uncontrolled myeloid cell growth. [18] Two homologous corepressor genes, BCOR (BCL6 corepressor) and BCORL1, are recurrently mutated in AML patients. [19] [20] BCOR works with multiple transcription factors and is known to play vital regulatory roles in embryonic development. [18] [19] Clinical results detected BCOR somatic mutations in ~4% of an unselected group of AML patients, and ~17% in a subset of patients who lack known AML-causing mutations. [18] [19] Similarly, BCORL1 is a corepressor that regulates cellular processes, [21] and was found to be mutated in ~6% of tested AML patients. [18] [20] These studies point out a strong association between corepressor mutations and AML. Further corepressor research may reveal potential therapeutic targets for AML and other diseases.

Therapeutic Potential

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

BCL6 upregulation is observed in cancers such as diffuse large B-cell lymphomas (DLBCLs), [23] [24] [25] [26] colorectal cancer, [27] [28] and lung cancer. [29] [30] BCL-6 corepressor, SMRT, NCoR, and other corepressors are able to interact with and transcriptionally repress BCL6. [23] [24] [25] [26] Small-molecule compounds, such as synthetic peptides that target BCL6 and corepressor interactions, [23] [24] as well as other protein-protein interaction inhibitors, [26] have been shown to effectively kill cancer cells.

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

Related Research Articles

In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splicing to create monocistronic mRNAs that are translated separately, i.e. several strands of mRNA that each encode a single gene product. The result of this is that the genes contained in the operon are either expressed together or not at all. Several genes must be co-transcribed to define an operon.

<span class="mw-page-title-main">EP300</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.

<span class="mw-page-title-main">HDAC1</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.

<span class="mw-page-title-main">Nuclear receptor co-repressor 1</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.

<span class="mw-page-title-main">Nuclear receptor co-repressor 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 2 (NCOR2) is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression. NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT) or T3 receptor-associating cofactor 1 (TRAC-1).

<span class="mw-page-title-main">Rev-ErbA alpha</span> Protein-coding gene in the species Homo sapiens

Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species.

<span class="mw-page-title-main">BCL6</span> Transcription factor for converting Naive T cells to TFH

Bcl-6 is a protein that in humans is encoded by the BCL6 gene. BCL6 is a master transcription factor for regulation of T follicular helper cells proliferation. BCL6 has three evolutionary conserved structural domains. The interaction of these domains with corepressors allows for germinal center development and leads to B cell proliferation.

<span class="mw-page-title-main">HDAC3</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 3 is an enzyme encoded by the HDAC3 gene in both humans and mice.

<span class="mw-page-title-main">SIN3A</span> Protein-coding gene in the species Homo sapiens

Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.

<span class="mw-page-title-main">Zinc finger and BTB domain-containing protein 16</span> Protein found in humans

Zinc finger and BTB domain-containing protein 16 is a protein that in humans is encoded by the ZBTB16 gene.

<span class="mw-page-title-main">HDAC4</span>

Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.

<span class="mw-page-title-main">CTBP1</span> Protein-coding gene in the species Homo sapiens

C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.

<span class="mw-page-title-main">RUNX1T1</span> Protein-coding gene in humans

Protein CBFA2T1 is a protein that in humans is encoded by the RUNX1T1 gene.

<span class="mw-page-title-main">Histone deacetylase 5</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 5 is an enzyme that in humans is encoded by the HDAC5 gene.

<span class="mw-page-title-main">MECOM</span> Protein-coding gene in the species Homo sapiens

MDS1 and EVI1 complex locus protein EVI1 (MECOM) also known as ecotropic virus integration site 1 protein homolog (EVI-1) or positive regulatory domain zinc finger protein 3 (PRDM3) is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both coexpression and coactivation of cell cycle genes.

<span class="mw-page-title-main">CTBP2</span> Protein-coding gene in the species Homo sapiens

C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the CTBP2 gene.

<span class="mw-page-title-main">BCL-6 corepressor</span> Protein-coding gene in humans

BCL-6 corepressor is a protein that in humans is encoded by the BCOR gene.

Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.

References

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  7. ↑ Schaefer U, Schmeier S, Bajic VB (January 2011). "TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins". Nucleic Acids Res. 39 (Database issue): D106–10. doi:10.1093/nar/gkq945. PMC   3013796 . PMID   20965969.
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