In the field of
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, a corepressor is a molecule that represses the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of
genes
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. In
prokaryotes
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
, corepressors are
small molecules
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
whereas in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
, corepressors are
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. A corepressor does not directly bind to
DNA, but instead indirectly regulates gene expression by binding to
repressors.
A corepressor
downregulates (or represses) the expression of genes by binding to and activating a repressor
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
. 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.
Function
Prokaryotes
In
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
s, the term corepressor is used to denote the activating
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
of a
repressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
protein. For example, the ''
E. coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
''
tryptophan repressor (TrpR) is only able to bind to DNA and repress transcription of the
''trp'' operon when its corepressor
tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α- carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
is bound to it. TrpR in the absence of tryptophan is known as an aporepressor and is inactive in repressing gene transcription.
Trp operon encodes enzymes responsible for the synthesis of tryptophan. Hence TrpR provides a
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
mechanism that regulates the
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of tryptophan.
In short tryptophan acts as a corepressor for its own biosynthesis.
Eukaryotes
In
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, a corepressor is a protein that binds to
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s.
In the absence of corepressors and in the presence of
coactivator
A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) 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 p ...
s, 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
Initiation is a rite of passage marking entrance or acceptance into a group or society. It could also be a formal admission to adulthood in a community or one of its formal components. In an extended sense, it can also signify a transformation ...
when bound to transcription factor/DNA complexes is by recruiting
histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s which
catalyze
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the removal of
acetyl
In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
groups from
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues. This increases the positive charge on
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
s which strengthens the
electrostatic
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...
attraction between the positively charged histones and negatively charged DNA, making the DNA less accessible for transcription.
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.
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.
Class I
histone deacetylases
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
are recruited by NCoR through SIN3, and NCoR directly binds to class II
histone deacetylases
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
.
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
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by l ...
(steroid receptor coactivator-1).
It is negatively and positively affected by MAPKKK (mitogen activated protein kinase kinase kinase) and casein kinase 2 phosphorylation, respectively.
SMRT has two major mechanisms: first, similar to NCoR, SMRT also recruits class I
histone deacetylases
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
through SIN3 and directly binds to class II
histone deacetylases
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
.
Second, it binds and sequesters components of the general transcriptional machinery, such as
transcription factor II B
Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and pro ...
.
Role in biological processes
Corepressors are known to regulate transcription through different activation and inactivation states.
NCoR and
SMRT act as a corepressor complex to regulate transcription by becoming activated once the ligand is bound.
Knockouts of NCoR resulted in embryo death, indicating its importance in erythrocytic, thymic, and neural system development.
Mutations in certain corepressors can result in deregulation of signals.
SMRT contributes to cardiac muscle development, with knockouts of the complex resulting in less developed muscle and improper development.
NCoR has also been found to be an important checkpoint in processes such as inflammation and
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
activation.
Recent evidence also suggests the role of corepressor
RIP140 in metabolic regulation of energy homeostasis.
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.
Acute myeloid leukemia (AML) is a highly lethal blood cancer characterized by uncontrolled myeloid cell growth.
Two homologous corepressor genes,
BCOR (BCL6 corepressor) and BCORL1, are recurrently mutated in
AML patients.
BCOR works with multiple transcription factors and is known to play vital regulatory roles in embryonic development.
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.
Similarly, BCORL1 is a corepressor that regulates cellular processes, and was found to be mutated in ~6% of tested
AML patients.
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.
BCL6 upregulation is observed in cancers such as
diffuse large B-cell lymphomas (DLBCLs),
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
, and
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
.
BCL-6 corepressor,
SMRT,
NCoR, and other corepressors are able to interact with and transcriptionally repress
BCL6.
Small-molecule compounds, such as synthetic
peptides
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
that target
BCL6 and corepressor interactions,
as well as other protein-protein interaction inhibitors,
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
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, making
LXR agonists like GW3965 a potential therapeutic strategy.
Ursodeoxycholic acid (UDCA), by upregulating the corepressor small heterodimer partner interacting leucine zipper protein (SMILE), inhibits the expression of IL-17, an inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, and suppresses Th17 cells, both implicated in
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
.
This effect is dose-dependent in humans, and
UCDA is thought to be another prospective agent of
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
therapy.
See also
*
Transcription coregulator
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 ...
*
TcoF-DB
The Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins (TcoF-DB) is a database that facilitates the exploration of proteins involved in the regulation of transcription in humans by binding to regulatory ...
References
External links
*
{{Transcription coregulators
Gene expression
Transcription coregulators