# Corepressor
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{{Short description|Molecule that represses the expression of genes}}
In [genetics](/source/genetics) and [molecular biology](/source/molecular_biology), a '''corepressor''' is a molecule that represses the [expression](/source/Gene_expression) of [genes](/source/Gene).[{{Cite book|url=http://link.springer.com/10.1007/978-3-662-10595-5|title=Transcriptional Corepressors: Mediators of Eukaryotic Gene Repression|date=2001|publisher=Springer Berlin Heidelberg|isbn=978-3-642-08709-7|editor-last=Privalsky|editor-first=Martin L.|series=Current Topics in Microbiology and Immunology|volume=254|location=Berlin, Heidelberg|language=en|doi=10.1007/978-3-662-10595-5|s2cid=8922796 }}] In [prokaryotes](/source/Prokaryote), corepressors are [small molecules](/source/Small_molecule) whereas in [eukaryotes](/source/Eukaryote), corepressors are [proteins](/source/Protein). A corepressor does not directly bind to [DNA](/source/DNA), but instead indirectly regulates gene expression by binding to [repressors](/source/Repressor).
A corepressor [downregulates](/source/Downregulation_and_upregulation) (or represses) the expression of genes by binding to and activating a repressor [transcription factor](/source/transcription_factor). The repressor in turn binds to a gene's [operator](/source/Operator_(biology)) sequence (segment of [DNA](/source/DNA) to which a transcription factor binds to regulate gene expression), thereby blocking transcription of that gene.
thumb|Corepressor Transcription Factor Complex on Regulatory Element
== Function ==
=== Prokaryotes ===
In [prokaryote](/source/prokaryote)s, the term corepressor is used to denote the activating [ligand](/source/ligand_(biochemistry)) of a [repressor](/source/repressor) protein. For example, the ''[E. coli](/source/Escherichia_coli)'' [tryptophan repressor](/source/tryptophan_repressor) (TrpR) is only able to bind to DNA and repress transcription of the [''trp'' operon](/source/trp_operon) when its corepressor [tryptophan](/source/tryptophan) is bound to it. TrpR in the absence of tryptophan is known as an aporepressor and is inactive in repressing gene transcription.[{{cite journal | vauthors = Evans PD, Jaseja M, Jeeves M, Hyde EI | title = NMR studies of the Escherichia coli Trp repressor.trpRs operator complex | journal = Eur. J. Biochem. | volume = 242 | issue = 3 | pages = 567–75 |date=December 1996 | pmid = 9022683 | doi = 10.1111/j.1432-1033.1996.0567r.x | doi-access = }}] Trp operon encodes enzymes responsible for the synthesis of tryptophan. Hence TrpR provides a [negative feedback](/source/negative_feedback) mechanism that regulates the [biosynthesis](/source/biosynthesis) of tryptophan.
In short tryptophan acts as a corepressor for its own biosynthesis.[{{cite book | vauthors = Foster JB, Slonczewski J | title = Microbiology: An Evolving Science | edition = Second | publisher = W. W. Norton & Company | location = New York | year = 2010 | isbn = 978-0-393-93447-2 }}]
=== Eukaryotes ===
In [eukaryote](/source/eukaryote)s, a corepressor is a protein that binds to [transcription factor](/source/transcription_factor)s.[{{cite journal | author = Jenster G | title = Coactivators and corepressors as mediators of nuclear receptor function: an update | journal = Mol. Cell. Endocrinol. | volume = 143 | issue = 1–2 | pages = 1–7 |date=August 1998 | pmid = 9806345 | doi = 10.1016/S0303-7207(98)00145-2 | s2cid = 26244186 }}] In the absence of corepressors and in the presence of [coactivator](/source/coactivator)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](/source/Transcription_(genetics)) when bound to transcription factor/DNA complexes is by recruiting [histone deacetylase](/source/histone_deacetylase)s which [catalyze](/source/catalysis) the removal of [acetyl](/source/acetyl) groups from [lysine](/source/lysine) residues. This increases the positive charge on [histone](/source/histone)s which strengthens the [electrostatic](/source/electrostatics) attraction between the positively charged histones and negatively charged DNA, making the DNA less accessible for transcription.[{{cite journal | author = Lazar MA | title = Nuclear receptor corepressors | journal = Nucl Recept Signal | volume = 1 | pages = e001 | year = 2003 | pmid = 16604174 | pmc = 1402229 | doi = 10.1621/nrs.01001 }}][{{cite journal |vauthors=Goodson M, Jonas BA, Privalsky MA|title=Corepressors: custom tailoring and alterations while you wait|journal= Nucl Recept Signal |volume= 3 |issue= Oct 21 |pages= e003 |year= 2005|article-number=nrs.03003 | doi = 10.1621/nrs.03003 |pmid= 16604171 |pmc=1402215}}]
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.[{{cite journal | vauthors = Schaefer U, Schmeier S, Bajic VB | title = TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins | journal = Nucleic Acids Res. | volume = 39 | issue = Database issue | pages = D106–10 |date=January 2011 | pmid = 20965969 | pmc = 3013796 | doi = 10.1093/nar/gkq945 }}]
== Examples of corepressors ==
=== NCoR ===
[NCoR](/source/Nuclear_receptor_co-repressor_1) (nuclear receptor co-repressor) directly binds to the D and E domains of nuclear receptors and represses their transcriptional activity.[{{Citation|last=Bolander|first=Franklyn F.|title=Hormonally Regulated Transcription Factors|date=2004|url=https://linkinghub.elsevier.com/retrieve/pii/B9780121112325500130|work=Molecular Endocrinology|pages=387–443|publisher=Elsevier|language=en|doi=10.1016/b978-012111232-5/50013-0|isbn=978-0-12-111232-5|access-date=2020-10-25|url-access=subscription}}][{{Cite journal|last=Chinnadurai|first=G|date=February 2002|title=CtBP, an Unconventional Transcriptional Corepressor in Development and Oncogenesis|journal=Molecular Cell|language=en|volume=9|issue=2|pages=213–224|doi=10.1016/S1097-2765(02)00443-4|pmid=11864595|doi-access=free}}][{{Citation|last=Kammer|first=Gary M.|title=Estrogen, Signal Transduction, and Systemic Lupus Erythematosus: Molecular Mechanisms|date=2004|url=https://linkinghub.elsevier.com/retrieve/pii/B9780124409057503753|work=Principles of Gender-Specific Medicine|pages=1082–1092|publisher=Elsevier|language=en|doi=10.1016/b978-012440905-7/50375-3|isbn=978-0-12-440905-7|access-date=2020-10-25|url-access=subscription}}] Class I [histone deacetylases](/source/Histone_deacetylase) are recruited by NCoR through SIN3, and NCoR directly binds to class II [histone deacetylases](/source/Histone_deacetylase).[{{Cite journal|last1=Kadamb|first1=Rama|last2=Mittal|first2=Shilpi|last3=Bansal|first3=Nidhi|last4=Batra|first4=Harish|last5=Saluja|first5=Daman|date=August 2013|title=Sin3: Insight into its transcription regulatory functions|url=https://linkinghub.elsevier.com/retrieve/pii/S0171933513000575|journal=European Journal of Cell Biology|language=en|volume=92|issue=8–9|pages=237–246|doi=10.1016/j.ejcb.2013.09.001|pmid=24189169|url-access=subscription}}]
=== Silencing mediator for retinoid and thyroid-hormone receptor===
[SMRT](/source/Nuclear_receptor_co-repressor_2) (silencing mediator of retinoic acid and thyroid hormone receptor), also known as [NCoR2](/source/Nuclear_receptor_co-repressor_2), is an alternatively spliced [SRC-1](/source/Nuclear_receptor_coactivator_1)(steroid receptor coactivator-1).[{{Cite journal|last=Rosenfeld|first=M. G.|date=2006-06-01|title=Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response|journal=Genes & Development|language=en|volume=20|issue=11|pages=1405–1428|doi=10.1101/gad.1424806|pmid=16751179|issn=0890-9369|doi-access=free}}][{{Cite journal|last1=Battaglia|first1=Sebastiano|last2=Maguire|first2=Orla|last3=Campbell|first3=Moray J.|date=2010|title=Transcription factor co-repressors in cancer biology: roles and targeting|url= |journal=International Journal of Cancer|volume=126|issue=11|language=en|pages=2511–9|doi=10.1002/ijc.25181|pmc=2847647|pmid=20091860}}]
NCoR and [SMRT](/source/Nuclear_receptor_co-repressor_2) act as a corepressor complex to regulate transcription by becoming activated once the ligand is bound.[{{Cite journal|last1=Christian|first1=Mark|last2=White|first2=Roger|last3=Parker|first3=Malcolm G.|date=August 2006|title=Metabolic regulation by the nuclear receptor corepressor RIP140|url=https://linkinghub.elsevier.com/retrieve/pii/S1043276006001056|journal=Trends in Endocrinology & Metabolism|language=en|volume=17|issue=6|pages=243–250|doi=10.1016/j.tem.2006.06.008|pmid=16815031|s2cid=45870845|url-access=subscription}}][{{Cite journal|last1=Ogawa|first1=S.|last2=Lozach|first2=J.|last3=Jepsen|first3=K.|last4=Sawka-Verhelle|first4=D.|last5=Perissi|first5=V.|last6=Sasik|first6=R.|last7=Rose|first7=D. W.|last8=Johnson|first8=R. S.|last9=Rosenfeld|first9=M. G.|last10=Glass|first10=C. K.|date=2004-10-05|title=A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=40|pages=14461–14466|doi=10.1073/pnas.0405786101|issn=0027-8424|pmc=521940|pmid=15452344|bibcode=2004PNAS..10114461O|doi-access=free}}] Knockouts of NCoR resulted in embryo death, indicating its importance in erythrocytic, thymic, and neural system development.[{{Cite journal|last1=Jepsen|first1=Kristen|last2=Hermanson|first2=Ola|last3=Onami|first3=Thandi M|last4=Gleiberman|first4=Anatoli S|last5=Lunyak|first5=Victoria|last6=McEvilly|first6=Robert J|last7=Kurokawa|first7=Riki|last8=Kumar|first8=Vivek|last9=Liu|first9=Forrest|last10=Seto|first10=Edward|last11=Hedrick|first11=Stephen M|date=September 2000|title=Combinatorial Roles of the Nuclear Receptor Corepressor in Transcription and Development|journal=Cell|language=en|volume=102|issue=6|pages=753–763|doi=10.1016/S0092-8674(00)00064-7|pmid=11030619|s2cid=15645977|doi-access=free}}]
Mutations in certain corepressors can result in deregulation of signals.[{{Cite journal|last=Privalsky|first=Martin L.|date=March 2004|title=The Role of Corepressors in Transcriptional Regulation by Nuclear Hormone Receptors|url=http://dx.doi.org/10.1146/annurev.physiol.66.032802.155556|journal=Annual Review of Physiology|volume=66|issue=1|pages=315–360|doi=10.1146/annurev.physiol.66.032802.155556|pmid=14977406|issn=0066-4278|url-access=subscription}}]
[Acute myeloid leukemia (AML)](/source/Acute_myeloid_leukemia) is a highly lethal blood cancer characterized by uncontrolled myeloid cell growth.[{{Cite journal|last1=Tiacci|first1=E.|last2=Grossmann|first2=V.|last3=Martelli|first3=M. P.|last4=Kohlmann|first4=A.|last5=Haferlach|first5=T.|last6=Falini|first6=B.|date=2011-12-30|title=The corepressors BCOR and BCORL1: two novel players in acute myeloid leukemia|journal=Haematologica|volume=97|issue=1|pages=3–5|doi=10.3324/haematol.2011.057901|pmid=22210327|pmc=3248923|issn=0390-6078|doi-access=free}}] Two homologous corepressor genes, [BCOR (BCL6 corepressor)](/source/BCL-6_corepressor) and BCORL1, are recurrently mutated in [AML](/source/Acute_myeloid_leukemia) patients.[{{Cite journal|last1=Grossmann|first1=Vera|last2=Tiacci|first2=Enrico|last3=Holmes|first3=Antony B.|last4=Kohlmann|first4=Alexander|last5=Martelli|first5=Maria Paola|last6=Kern|first6=Wolfgang|last7=Spanhol-Rosseto|first7=Ariele|last8=Klein|first8=Hans-Ulrich|last9=Dugas|first9=Martin|last10=Schindela|first10=Sonja|last11=Trifonov|first11=Vladimir|date=2011-12-01|title=Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype|journal=Blood|volume=118|issue=23|pages=6153–6163|doi=10.1182/blood-2011-07-365320|pmid=22012066|issn=0006-4971|doi-access=free}}][{{Cite journal|last1=Li|first1=Meng|last2=Collins|first2=Roxane|last3=Jiao|first3=Yuchen|last4=Ouillette|first4=Peter|last5=Bixby|first5=Dale|last6=Erba|first6=Harry|last7=Vogelstein|first7=Bert|last8=Kinzler|first8=Kenneth W.|last9=Papadopoulos|first9=Nickolas|last10=Malek|first10=Sami N.|date=2011-11-24|title=Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia|journal=Blood|volume=118|issue=22|pages=5914–5917|doi=10.1182/blood-2011-05-356204|pmid=21989985|pmc=3228503|issn=0006-4971|doi-access=free}}] [BCOR](/source/BCOR_(gene)) works with multiple transcription factors and is known to play vital regulatory roles in embryonic development.[{{Cite journal|last1=Pagan|first1=Julia K.|last2=Arnold|first2=Jeremy|last3=Hanchard|first3=Kim J.|last4=Kumar|first4=Raman|last5=Bruno|first5=Tiziana|last6=Jones|first6=Mathew J. K.|last7=Richard|first7=Derek J.|last8=Forrest|first8=Alistair|last9=Spurdle|first9=Amanda|last10=Verdin|first10=Eric|last11=Crossley|first11=Merlin|date=2007-03-22|title=A Novel Corepressor, BCoR-L1, Represses Transcription through an Interaction with CtBP|journal=Journal of Biological Chemistry|volume=282|issue=20|pages=15248–15257|doi=10.1074/jbc.m700246200|pmid=17379597|issn=0021-9258|doi-access=free}}] and was found to be mutated in ~6% of tested [AML](/source/Acute_myeloid_leukemia) patients.[{{Cite journal|last1=Vaiopoulos|first1=Aristeidis G.|last2=Kostakis|first2=Ioannis D.|last3=Athanasoula|first3=Kalliopi Ch.|last4=Papavassiliou|first4=Athanasios G.|date=June 2012|title=Targeting transcription factor corepressors in tumor cells|journal=Cellular and Molecular Life Sciences|language=en|volume=69|issue=11|pages=1745–1753|doi=10.1007/s00018-012-0986-5|pmid=22527719|s2cid=16407925|issn=1420-682X|pmc=11114811}}]
[BCL6](/source/BCL6) upregulation is observed in cancers such as [diffuse large B-cell lymphomas (DLBCLs)](/source/Diffuse_large_B-cell_lymphoma),[{{Cite journal|last1=Cerchietti|first1=Leandro C.|last2=Ghetu|first2=Alexandru F.|last3=Zhu|first3=Xiao|last4=Da Silva|first4=Gustavo F.|last5=Zhong|first5=Shijun|last6=Matthews|first6=Marilyn|last7=Bunting|first7=Karen L.|last8=Polo|first8=Jose M.|last9=Farès|first9=Christophe|last10=Arrowsmith|first10=Cheryl H.|last11=Yang|first11=Shao Ning|date=April 2010|title=A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo|url= |journal=Cancer Cell|language=en|volume=17|issue=4|pages=400–411|doi=10.1016/j.ccr.2009.12.050|pmc=2858395|pmid=20385364}}][{{Cite journal|last1=Cerchietti|first1=Leandro C.|last2=Yang|first2=Shao Ning|last3=Shaknovich|first3=Rita|last4=Hatzi|first4=Katerina|last5=Polo|first5=Jose M.|last6=Chadburn|first6=Amy|last7=Dowdy|first7=Steven F.|last8=Melnick|first8=Ari|date=2009-04-09|title=A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo|url=https://ashpublications.org/blood/article/113/15/3397/24984/A-peptomimetic-inhibitor-of-BCL6-with-potent|journal=Blood|language=en|volume=113|issue=15|pages=3397–3405|doi=10.1182/blood-2008-07-168773|issn=0006-4971|pmc=2668844|pmid=18927431}}][{{Cite journal|last1=Parekh|first1=Samir|last2=Privé|first2=Gilbert|last3=Melnick|first3=Ari|date=January 2008|title=Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas|url= |journal=Leukemia & Lymphoma|language=en|volume=49|issue=5|pages=874–882|doi=10.1080/10428190801895345|issn=1042-8194|pmc=2748726|pmid=18452090}}][{{Cite journal|last1=Yasui|first1=Takeshi|last2=Yamamoto|first2=Takeshi|last3=Sakai|first3=Nozomu|last4=Asano|first4=Kouhei|last5=Takai|first5=Takafumi|last6=Yoshitomi|first6=Yayoi|last7=Davis|first7=Melinda|last8=Takagi|first8=Terufumi|last9=Sakamoto|first9=Kotaro|last10=Sogabe|first10=Satoshi|last11=Kamada|first11=Yusuke|date=September 2017|title=Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design|journal=Bioorganic & Medicinal Chemistry|language=en|volume=25|issue=17|pages=4876–4886|doi=10.1016/j.bmc.2017.07.037|pmid=28760529|doi-access=free}}] [colorectal cancer](/source/colorectal_cancer),[{{Cite journal|last1=Sena|first1=Paola|last2=Mariani|first2=Francesco|last3=Benincasa|first3=Marta|last4=De Leon|first4=Maurizio Ponz|last5=Di Gregorio|first5=Carmela|last6=Mancini|first6=Stefano|last7=Cavani|first7=Francesco|last8=Smargiassi|first8=Alberto|last9=Palumbo|first9=Carla|last10=Roncucci|first10=Luca|date=January 2014|title=Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis|journal=Oncology Reports|language=en|volume=31|issue=1|pages=103–110|doi=10.3892/or.2013.2846|pmid=24220798|issn=1021-335X|doi-access=free|hdl=11380/1011113|hdl-access=free}}][{{Cite journal|last1=Sun|first1=Naihui|last2=Zhang|first2=Liang|last3=Zhang|first3=Chongguang|last4=Yuan|first4=Yuan|date=December 2020|title=miR-144-3p inhibits cell proliferation of colorectal cancer cells by targeting BCL6 via inhibition of Wnt/β-catenin signaling|url= |journal=Cellular & Molecular Biology Letters|language=en|volume=25|issue=1|pages=19|doi=10.1186/s11658-020-00210-3|issn=1425-8153|pmc=7079415|pmid=32206063 |doi-access=free }}] and [lung cancer](/source/lung_cancer).[{{Cite journal|last1=Deb|first1=Dhruba|last2=Rajaram|first2=Satwik|last3=Larsen|first3=Jill E.|last4=Dospoy|first4=Patrick D.|last5=Marullo|first5=Rossella|last6=Li|first6=Long Shan|last7=Avila|first7=Kimberley|last8=Xue|first8=Fengtian|last9=Cerchietti|first9=Leandro|last10=Minna|first10=John D.|last11=Altschuler|first11=Steven J.|date=2017-06-01|title=Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers|url= |journal=Cancer Research|language=en|volume=77|issue=11|pages=3070–3081|doi=10.1158/0008-5472.CAN-15-3052|issn=0008-5472|pmc=5489259|pmid=28377453}}] [BCL-6 corepressor](/source/BCL-6_corepressor), [SMRT](/source/Silencing_mediator_for_retinoid_and_thyroid-hormone_receptor), [NCoR](/source/Nuclear_receptor_co-repressor_1), and other corepressors are able to interact with and transcriptionally repress [BCL6](/source/BCL6).[{{Cite journal|last1=Venteclef|first1=N.|last2=Jakobsson|first2=T.|last3=Ehrlund|first3=A.|last4=Damdimopoulos|first4=A.|last5=Mikkonen|first5=L.|last6=Ellis|first6=E.|last7=Nilsson|first7=L.-M.|last8=Parini|first8=P.|last9=Janne|first9=O. A.|last10=Gustafsson|first10=J.-A.|last11=Steffensen|first11=K. R.|date=2010-02-15|title=GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXR in the hepatic acute phase response|journal=Genes & Development|language=en|volume=24|issue=4|pages=381–395|doi=10.1101/gad.545110|issn=0890-9369|pmc=2816737|pmid=20159957}}][{{Cite journal|last1=Yoon|first1=Chong-Hyeon|last2=Kwon|first2=Yong-Jin|last3=Lee|first3=Sang-Won|last4=Park|first4=Yong-Beom|last5=Lee|first5=Soo-Kon|last6=Park|first6=Min-Chan|date=January 2013|title=Activation of Liver X Receptors Suppresses Inflammatory Gene Expressions and Transcriptional Corepressor Clearance in Rheumatoid Arthritis Fibroblast Like Synoviocytes|url=http://link.springer.com/10.1007/s10875-012-9799-4|journal=Journal of Clinical Immunology|language=en|volume=33|issue=1|pages=190–199|doi=10.1007/s10875-012-9799-4|pmid=22990668|s2cid=15965750|issn=0271-9142|url-access=subscription}}] [Ursodeoxycholic acid (UDCA)](/source/Ursodeoxycholic_acid), by upregulating the corepressor [CREBZF](/source/CREBZF) (small heterodimer partner interacting leucine zipper protein, SMILE), inhibits the expression of [IL-17](/source/Interleukin_17), an [inflammatory cytokine](/source/inflammatory_cytokine), and suppresses [Th17 cell](/source/Th17_cell)s, both implicated in [rheumatoid arthritis](/source/rheumatoid_arthritis).[{{Cite journal|last1=Lee|first1=Eun-Jung|last2=Kwon|first2=Jeong-Eun|last3=Park|first3=Min-Jung|last4=Jung|first4=Kyung-Ah|last5=Kim|first5=Da-Som|last6=Kim|first6=Eun-Kyung|last7=Lee|first7=Seung Hoon|last8=Choi|first8=Jong Young|last9=Park|first9=Sung-Hwan|last10=Cho|first10=Mi-La|date=August 2017|title=Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE|url=https://linkinghub.elsevier.com/retrieve/pii/S0165247816302401|journal=Immunology Letters|language=en|volume=188|pages=1–8|doi=10.1016/j.imlet.2017.05.011|pmid=28539269|url-access=subscription}}][{{Cite journal|last1=Sarkar|first1=Sujata|last2=Fox|first2=David A.|date=May 2010|title=Targeting IL-17 and Th17 Cells in Rheumatoid Arthritis|url=https://linkinghub.elsevier.com/retrieve/pii/S0889857X10000189|journal=Rheumatic Disease Clinics of North America|language=en|volume=36|issue=2|pages=345–366|doi=10.1016/j.rdc.2010.02.006|pmid=20510238|url-access=subscription}}] This effect is dose-dependent in humans, and [UCDA](/source/Ursodeoxycholic_acid) is thought to be another prospective agent of [rheumatoid arthritis](/source/rheumatoid_arthritis) therapy.