A corepressordownregulates (or represses) the expression of genes by binding to and activating a repressortranscription factor. The repressor in turn binds to a gene'soperator sequence (segment ofDNA to which a transcription factor binds to regulate gene expression), thereby blocking transcription of that gene.
Corepressor Transcription Factor Complex on Regulatory Element
Inprokaryotes, the term corepressor is used to denote the activatingligand of arepressor protein. For example, theE. colitryptophan repressor (TrpR) is only able to bind to DNA and repress transcription of thetrp operon when its corepressortryptophan 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 anegative feedback mechanism that regulates thebiosynthesis of tryptophan.
In short tryptophan acts as a corepressor for its own biosynthesis.[3]
Ineukaryotes, a corepressor is a protein that binds totranscription factors.[4] In the absence of corepressors and in the presence ofcoactivators, 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 transcriptionalinitiation when bound to transcription factor/DNA complexes is by recruitinghistone deacetylases whichcatalyze the removal ofacetyl groups fromlysine residues. This increases the positive charge onhistones which strengthens theelectrostatic 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]
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 Ihistone deacetylases are recruited by NCoR through SIN3, and NCoR directly binds to class IIhistone deacetylases.[8][10][11]
Silencing mediator for retinoid and thyroid-hormone receptor
SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), also known asNCoR2, is an alternatively splicedSRC-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 Ihistone deacetylases through SIN3 and directly binds to class IIhistone deacetylases.[8] Second, it binds and sequesters components of the general transcriptional machinery, such astranscription factor II B.[8][10]
Corepressors are known to regulate transcription through different activation and inactivation states.[12][13]
NCoR andSMRT 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 andmacrophage activation.[15]
Recent evidence also suggests the role of corepressorRIP140 in metabolic regulation of energy homeostasis.[14]
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 inAML patients.[19][20]BCOR works with multiple transcription factors and is known to play vital regulatory roles in embryonic development.[18][19] Clinical results detectedBCOR somatic mutations in ~4% of an unselected group ofAML patients, and ~17% in a subset of patients who lack knownAML-causing mutations.[18][19] Similarly, BCORL1 is a corepressor that regulates cellular processes,[21] and was found to be mutated in ~6% of testedAML patients.[18][20] These studies point out a strong association between corepressor mutations andAML. Further corepressor research may reveal potential therapeutic targets forAML and other diseases.
^Evans PD, Jaseja M, Jeeves M, Hyde EI (December 1996). "NMR studies of the Escherichia coli Trp repressor.trpRs operator complex".Eur. J. Biochem.242 (3):567–75.doi:10.1111/j.1432-1033.1996.0567r.x.PMID9022683.
^Foster JB, Slonczewski J (2010).Microbiology: An Evolving Science (Second ed.). New York: W. W. Norton & Company.ISBN978-0-393-93447-2.
