Biology:Corepressor

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Short description: Molecule that represses the expression of genes

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 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

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

References

  1. ↑ Privalsky, Martin L., ed (2001) (in en). Transcriptional Corepressors: Mediators of Eukaryotic Gene Repression. Current Topics in Microbiology and Immunology. 254. Berlin, Heidelberg: Springer Berlin Heidelberg. doi:10.1007/978-3-662-10595-5. ISBN 978-3-642-08709-7. http://link.springer.com/10.1007/978-3-662-10595-5. 
  2. ↑ "NMR studies of the Escherichia coli Trp repressor.trpRs operator complex". Eur. J. Biochem. 242 (3): 567–75. December 1996. doi:10.1111/j.1432-1033.1996.0567r.x. PMID 9022683. 
  3. ↑ Microbiology: An Evolving Science (Second ed.). New York: W. W. Norton & Company. 2010. ISBN 978-0-393-93447-2. 
  4. ↑ Jenster G (August 1998). "Coactivators and corepressors as mediators of nuclear receptor function: an update". Mol. Cell. Endocrinol. 143 (1–2): 1–7. doi:10.1016/S0303-7207(98)00145-2. PMID 9806345. 
  5. ↑ Lazar MA (2003). "Nuclear receptor corepressors". Nucl Recept Signal 1: e001. doi:10.1621/nrs.01001. PMID 16604174. 
  6. ↑ "Corepressors: custom tailoring and alterations while you wait". Nucl Recept Signal 3 (Oct 21): e003. 2005. doi:10.1621/nrs.03003. PMID 16604171. 
  7. ↑ "TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins". Nucleic Acids Res. 39 (Database issue): D106–10. January 2011. doi:10.1093/nar/gkq945. PMID 20965969. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Bolander, Franklyn F. (2004), "Hormonally Regulated Transcription Factors" (in en), Molecular Endocrinology (Elsevier): pp. 387–443, doi:10.1016/b978-012111232-5/50013-0, ISBN 978-0-12-111232-5, https://linkinghub.elsevier.com/retrieve/pii/B9780121112325500130, retrieved 2020-10-25 
  9. ↑ 9.0 9.1 Chinnadurai, G (February 2002). "CtBP, an Unconventional Transcriptional Corepressor in Development and Oncogenesis" (in en). Molecular Cell 9 (2): 213–224. doi:10.1016/S1097-2765(02)00443-4. PMID 11864595. 
  10. ↑ 10.0 10.1 10.2 Kammer, Gary M. (2004), "Estrogen, Signal Transduction, and Systemic Lupus Erythematosus: Molecular Mechanisms" (in en), Principles of Gender-Specific Medicine (Elsevier): pp. 1082–1092, doi:10.1016/b978-012440905-7/50375-3, ISBN 978-0-12-440905-7, https://linkinghub.elsevier.com/retrieve/pii/B9780124409057503753, retrieved 2020-10-25 
  11. ↑ Kadamb, Rama; Mittal, Shilpi; Bansal, Nidhi; Batra, Harish; Saluja, Daman (August 2013). "Sin3: Insight into its transcription regulatory functions" (in en). European Journal of Cell Biology 92 (8–9): 237–246. doi:10.1016/j.ejcb.2013.09.001. PMID 24189169. https://linkinghub.elsevier.com/retrieve/pii/S0171933513000575. 
  12. ↑ 12.0 12.1 Rosenfeld, M. G. (2006-06-01). "Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response" (in en). Genes & Development 20 (11): 1405–1428. doi:10.1101/gad.1424806. ISSN 0890-9369. PMID 16751179. 
  13. ↑ 13.0 13.1 13.2 13.3 Battaglia, Sebastiano; Maguire, Orla; Campbell, Moray J. (2010). "Transcription factor co-repressors in cancer biology: roles and targeting" (in en). International Journal of Cancer 126 (11): 2511–9. doi:10.1002/ijc.25181. PMID 20091860. 
  14. ↑ 14.0 14.1 Christian, Mark; White, Roger; Parker, Malcolm G. (August 2006). "Metabolic regulation by the nuclear receptor corepressor RIP140" (in en). Trends in Endocrinology & Metabolism 17 (6): 243–250. doi:10.1016/j.tem.2006.06.008. PMID 16815031. https://linkinghub.elsevier.com/retrieve/pii/S1043276006001056. 
  15. ↑ 15.0 15.1 15.2 Ogawa, S.; Lozach, J.; Jepsen, K.; Sawka-Verhelle, D.; Perissi, V.; Sasik, R.; Rose, D. W.; Johnson, R. S. et al. (2004-10-05). "A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation" (in en). Proceedings of the National Academy of Sciences 101 (40): 14461–14466. doi:10.1073/pnas.0405786101. ISSN 0027-8424. PMID 15452344. Bibcode: 2004PNAS..10114461O. 
  16. ↑ Jepsen, Kristen; Hermanson, Ola; Onami, Thandi M; Gleiberman, Anatoli S; Lunyak, Victoria; McEvilly, Robert J; Kurokawa, Riki; Kumar, Vivek et al. (September 2000). "Combinatorial Roles of the Nuclear Receptor Corepressor in Transcription and Development" (in en). Cell 102 (6): 753–763. doi:10.1016/S0092-8674(00)00064-7. PMID 11030619. 
  17. ↑ Privalsky, Martin L. (March 2004). "The Role of Corepressors in Transcriptional Regulation by Nuclear Hormone Receptors". Annual Review of Physiology 66 (1): 315–360. doi:10.1146/annurev.physiol.66.032802.155556. ISSN 0066-4278. PMID 14977406. http://dx.doi.org/10.1146/annurev.physiol.66.032802.155556. 
  18. ↑ 18.0 18.1 18.2 18.3 Tiacci, E.; Grossmann, V.; Martelli, M. P.; Kohlmann, A.; Haferlach, T.; Falini, B. (2011-12-30). "The corepressors BCOR and BCORL1: two novel players in acute myeloid leukemia". Haematologica 97 (1): 3–5. doi:10.3324/haematol.2011.057901. ISSN 0390-6078. PMID 22210327. 
  19. ↑ 19.0 19.1 19.2 Grossmann, Vera; Tiacci, Enrico; Holmes, Antony B.; Kohlmann, Alexander; Martelli, Maria Paola; Kern, Wolfgang; Spanhol-Rosseto, Ariele; Klein, Hans-Ulrich et al. (2011-12-01). "Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype". Blood 118 (23): 6153–6163. doi:10.1182/blood-2011-07-365320. ISSN 0006-4971. PMID 22012066. 
  20. ↑ 20.0 20.1 Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W. et al. (2011-11-24). "Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia". Blood 118 (22): 5914–5917. doi:10.1182/blood-2011-05-356204. ISSN 0006-4971. PMID 21989985. 
  21. ↑ Pagan, Julia K.; Arnold, Jeremy; Hanchard, Kim J.; Kumar, Raman; Bruno, Tiziana; Jones, Mathew J. K.; Richard, Derek J.; Forrest, Alistair et al. (2007-03-22). "A Novel Corepressor, BCoR-L1, Represses Transcription through an Interaction with CtBP". Journal of Biological Chemistry 282 (20): 15248–15257. doi:10.1074/jbc.m700246200. ISSN 0021-9258. PMID 17379597. 
  22. ↑ Vaiopoulos, Aristeidis G.; Kostakis, Ioannis D.; Athanasoula, Kalliopi Ch.; Papavassiliou, Athanasios G. (June 2012). "Targeting transcription factor corepressors in tumor cells" (in en). Cellular and Molecular Life Sciences 69 (11): 1745–1753. doi:10.1007/s00018-012-0986-5. ISSN 1420-682X. PMID 22527719. http://link.springer.com/10.1007/s00018-012-0986-5. 
  23. ↑ 23.0 23.1 23.2 Cerchietti, Leandro C.; Ghetu, Alexandru F.; Zhu, Xiao; Da Silva, Gustavo F.; Zhong, Shijun; Matthews, Marilyn; Bunting, Karen L.; Polo, Jose M. et al. (April 2010). "A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo" (in en). Cancer Cell 17 (4): 400–411. doi:10.1016/j.ccr.2009.12.050. PMID 20385364. 
  24. ↑ 24.0 24.1 24.2 Cerchietti, Leandro C.; Yang, Shao Ning; Shaknovich, Rita; Hatzi, Katerina; Polo, Jose M.; Chadburn, Amy; Dowdy, Steven F.; Melnick, Ari (2009-04-09). "A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo" (in en). Blood 113 (15): 3397–3405. doi:10.1182/blood-2008-07-168773. ISSN 0006-4971. PMID 18927431. PMC 2668844. https://ashpublications.org/blood/article/113/15/3397/24984/A-peptomimetic-inhibitor-of-BCL6-with-potent. 
  25. ↑ 25.0 25.1 Parekh, Samir; Privé, Gilbert; Melnick, Ari (January 2008). "Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas" (in en). Leukemia & Lymphoma 49 (5): 874–882. doi:10.1080/10428190801895345. ISSN 1042-8194. PMID 18452090. 
  26. ↑ 26.0 26.1 26.2 Yasui, Takeshi; Yamamoto, Takeshi; Sakai, Nozomu; Asano, Kouhei; Takai, Takafumi; Yoshitomi, Yayoi; Davis, Melinda; Takagi, Terufumi et al. (September 2017). "Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design" (in en). Bioorganic & Medicinal Chemistry 25 (17): 4876–4886. doi:10.1016/j.bmc.2017.07.037. PMID 28760529. 
  27. ↑ Sena, Paola; Mariani, Francesco; Benincasa, Marta; De Leon, Maurizio Ponz; Di Gregorio, Carmela; Mancini, Stefano; Cavani, Francesco; Smargiassi, Alberto et al. (January 2014). "Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis" (in en). Oncology Reports 31 (1): 103–110. doi:10.3892/or.2013.2846. ISSN 1021-335X. PMID 24220798. 
  28. ↑ Sun, Naihui; Zhang, Liang; Zhang, Chongguang; Yuan, Yuan (December 2020). "miR-144-3p inhibits cell proliferation of colorectal cancer cells by targeting BCL6 via inhibition of Wnt/β-catenin signaling" (in en). Cellular & Molecular Biology Letters 25 (1): 19. doi:10.1186/s11658-020-00210-3. ISSN 1425-8153. PMID 32206063. 
  29. ↑ Deb, Dhruba; Rajaram, Satwik; Larsen, Jill E.; Dospoy, Patrick D.; Marullo, Rossella; Li, Long Shan; Avila, Kimberley; Xue, Fengtian et al. (2017-06-01). "Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers" (in en). Cancer Research 77 (11): 3070–3081. doi:10.1158/0008-5472.CAN-15-3052. ISSN 0008-5472. PMID 28377453. 
  30. ↑ Sun, Chengcao; Li, Shujun; Yang, Cuili; Xi, Yongyong; Wang, Liang; Zhang, Feng; Li, Dejia (February 2016). "MicroRNA-187-3p mitigates non-small cell lung cancer (NSCLC) development through down-regulation of BCL6" (in en). Biochemical and Biophysical Research Communications 471 (1): 82–88. doi:10.1016/j.bbrc.2016.01.175. PMID 26845350. https://linkinghub.elsevier.com/retrieve/pii/S0006291X16301759. 
  31. ↑ Venteclef, N.; Jakobsson, T.; Ehrlund, A.; Damdimopoulos, A.; Mikkonen, L.; Ellis, E.; Nilsson, L.-M.; Parini, P. et al. (2010-02-15). "GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXR in the hepatic acute phase response" (in en). Genes & Development 24 (4): 381–395. doi:10.1101/gad.545110. ISSN 0890-9369. PMID 20159957. 
  32. ↑ Yoon, Chong-Hyeon; Kwon, Yong-Jin; Lee, Sang-Won; Park, Yong-Beom; Lee, Soo-Kon; Park, Min-Chan (January 2013). "Activation of Liver X Receptors Suppresses Inflammatory Gene Expressions and Transcriptional Corepressor Clearance in Rheumatoid Arthritis Fibroblast Like Synoviocytes" (in en). Journal of Clinical Immunology 33 (1): 190–199. doi:10.1007/s10875-012-9799-4. ISSN 0271-9142. PMID 22990668. http://link.springer.com/10.1007/s10875-012-9799-4. 
  33. ↑ 33.0 33.1 Lee, Eun-Jung; Kwon, Jeong-Eun; Park, Min-Jung; Jung, Kyung-Ah; Kim, Da-Som; Kim, Eun-Kyung; Lee, Seung Hoon; Choi, Jong Young et al. (August 2017). "Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE" (in en). Immunology Letters 188: 1–8. doi:10.1016/j.imlet.2017.05.011. PMID 28539269. https://linkinghub.elsevier.com/retrieve/pii/S0165247816302401. 
  34. ↑ Sarkar, Sujata; Fox, David A. (May 2010). "Targeting IL-17 and Th17 Cells in Rheumatoid Arthritis" (in en). Rheumatic Disease Clinics of North America 36 (2): 345–366. doi:10.1016/j.rdc.2010.02.006. PMID 20510238. https://linkinghub.elsevier.com/retrieve/pii/S0889857X10000189. 

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