Coactivator (genetics)
![](https://upload.wikimedia.org/wikipedia/commons/thumb/0/08/Type_ii_nuclear_receptor_action.png/457px-Type_ii_nuclear_receptor_action.png)
Acoactivatoris a type oftranscriptional coregulatorthat binds to anactivator(atranscription factor) to increase the rate oftranscriptionof ageneor set of genes.[1]The activator contains aDNA binding domainthat binds either to a DNApromotersite or a specific DNAregulatory sequencecalled anenhancer.[2][3]Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasinggene expression.[3][4][5]The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.[2]
Some coactivators also havehistone acetyltransferase(HAT) activity. HATs form large multiprotein complexes that weaken the association ofhistonesto DNA byacetylatingtheN-terminalhistone tail. This provides more space for the transcription machinery to bind to the promoter, therefore increasing gene expression.[1][4]
Activators are found in all livingorganisms,but coactivator proteins are typically only found in eukaryotes because they are more complex and require a more intricate mechanism for gene regulation.[1][4]In eukaryotes, coactivators are usually proteins that are localized in the nucleus.[1][6]
Mechanism
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/d/d0/Histone_acetylation_and_deacetylation.jpg/400px-Histone_acetylation_and_deacetylation.jpg)
Some coactivators indirectly regulate gene expression by binding to an activator and inducing aconformational changethat then allows the activator to bind to the DNA enhancer or promoter sequence.[2][7][8]Once the activator-coactivator complex binds to the enhancer, RNA polymerase II and other general transcription machinery are recruited to the DNA and transcription begins.[9]
Histone acetyltransferase
[edit]Nuclear DNAis normally wrapped tightly around histones, making it hard or impossible for the transcription machinery to access the DNA. This association is due primarily to theelectrostatic attractionbetween the DNA and histones as the DNAphosphatebackbone is negatively charged and histones are rich in lysine residues, which are positively charged.[10]The tight DNA-histone association prevents the transcription of DNA into RNA.
Many coactivators have histone acetyltransferase (HAT) activity meaning that they can acetylate specificlysineresidues on the N-terminal tails of histones.[4][7][11]In this method, an activator binds to an enhancer site and recruits a HAT complex that then acetylates nucleosomal promoter-bound histones by neutralizing the positively charged lysine residues.[7][11]This charge neutralization causes the histones to have a weaker bond to the negatively charged DNA, which relaxes the chromatin structure, allowing other transcription factors or transcription machinery to bind to the promoter (transcription initiation).[4][11]Acetylation by HAT complexes may also help keep chromatin open throughout the process of elongation, increasing the speed of transcription.[4]
![](https://upload.wikimedia.org/wikipedia/commons/thumb/0/06/Protein-acetylation-nterminal.svg/400px-Protein-acetylation-nterminal.svg.png)
Acetylation of the N-terminal histone tail is one of the most common protein modifications found in eukaryotes, with about 85% of all human proteins being acetylated.[12]Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts.[11][12]
HATs function similarly to N-terminal acetyltransferases (NATs) but their acetylation is reversible unlike in NATs.[13]HAT mediated histone acetylation is reversed using histone deacetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones.[4][7][11]This causes the chromatin to close back up from their relaxed state, making it difficult for the transcription machinery to bind to the promoter, thus repressing gene expression.[4][7]
Examples of coactivators that display HAT activity includeCARM1,CBPandEP300.[14][15]
Corepression
[edit]Many coactivators also function ascorepressorsunder certain circumstances.[5][9]Cofactors such asTAF1andBTAF1can initiate transcription in the presence of an activator (act as a coactivator) and repress basal transcription in the absence of an activator (act as a corepressor).[9]
Significance
[edit]Biological significance
[edit]Transcriptional regulation is one of the most common ways for an organism to alter gene expression.[16]The use of activation and coactivation allows for greater control over when, where and how much of a protein is produced.[1][7][16]This enables each cell to be able to quickly respond to environmental or physiological changes and helps to mitigate any damage that may occur if it were otherwise unregulated.[1][7]
Associated disorders
[edit]Mutationsto coactivator genes leading to loss or gain of protein function have been linked to diseases and disorders such asbirth defects,cancer(especially hormone dependent cancers),neurodevelopmental disordersandintellectual disability(ID), among many others.[17][5]Dysregulation leading to the over- or under-expression of coactivators can detrimentally interact with many drugs (especiallyanti-hormonedrugs) and has been implicated in cancer,fertilityissues and neurodevelopmental andneuropsychiatric disorders.[5]For a specific example, dysregulation ofCREB-binding protein(CBP)—which acts as a coactivator for numerous transcription factors within the central nervous system (CNS), reproductive system, thymus and kidneys—has been linked toHuntington's disease,leukaemia,Rubinstein-Taybi syndrome,neurodevelopmental disorders and deficits of theimmune system,hematopoiesisandskeletal musclefunction.[14][18]
As drug targets
[edit]Coactivators are promising targets for drug therapies in the treatment of cancer,metabolic disorder,cardiovascular diseaseandtype 2 diabetes,along with many other disorders.[5][19]For example, the steroid receptor coactivator (SCR)NCOA3is often overexpressed inbreast cancer,so the development of an inhibitor molecule that targets this coactivator and decreases its expression could be used as a potential treatment for breast cancer.[15][20]
Because transcription factors control many different biological processes, they are ideal targets for drug therapy.[14][21]The coactivators that regulate them can be easily replaced with a synthetic ligand that allows for control over an increase or decrease in gene expression.[14]
Further technological advances will provide new insights into the function and regulation of coactivators at a whole-organism level and elucidate their role in human disease, which will hopefully provide better targets for future drug therapies.[14][15]
Known coactivators
[edit]To date there are more than 300 known coregulators.[15]Some examples of these coactivators include:[22]
- ARA54targetsandrogen receptors
- ATXN7L3targets several members of thenuclear receptorsuperfamily
- BCL3targets 9-cis retinoic acid receptor (RXR)
- CBPtargets many transcription factors
- CDC25Btargetssteroid receptors
- COPS5targets several nuclear receptors
- DDCtargets androgen receptors
- EP300targets many transcription factors
- KAT5targets many nuclear receptors
- KDM1Atargets androgen receptors
- Steroid receptor coactivator (SRC) family
- YAPtargets transcription factors
- WWTR1targets transcription factors
See also
[edit]References
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- ^abcdefghBrown CE, Lechner T, Howe L, Workman JL (January 2000). "The many HATs of transcription coactivators".Trends in Biochemical Sciences.25(1): 15–9.doi:10.1016/S0968-0004(99)01516-9.PMID10637607.
- ^abcdeKumar R, O'Malley BW (2008).NR coregulators and human diseases.Hackensack, N.J.: World Scientific.ISBN978-981-270-536-5.OCLC261137374.
- ^Vosnakis N, Koch M, Scheer E, Kessler P, Mély Y, Didier P, Tora L (September 2017)."Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription".The EMBO Journal.36(18): 2710–2725.doi:10.15252/embj.201696035.PMC5599802.PMID28724529.
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- ^Scholes NS, Weinzierl RO (May 2016)."Molecular Dynamics of" Fuzzy "Transcriptional Activator-Coactivator Interactions".PLOS Computational Biology.12(5): e1004935.Bibcode:2016PLSCB..12E4935S.doi:10.1371/journal.pcbi.1004935.PMC4866707.PMID27175900.
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- ^Decher, Gero (1997-08-29). "Fuzzy Nanoassemblies: Toward Layered Polymeric Multicomposites".Science.277(5330): 1232–1237.doi:10.1126/science.277.5330.1232.ISSN0036-8075.
- ^abcdeHermanson O, Glass CK, Rosenfeld MG (2002). "Nuclear receptor coregulators: multiple modes of modification".Trends in Endocrinology and Metabolism.13(2): 55–60.doi:10.1016/s1043-2760(01)00527-6.PMID11854019.S2CID38649132.
- ^abVan Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T (July 2011)."NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation".PLOS Genetics.7(7): e1002169.doi:10.1371/journal.pgen.1002169.PMC3131286.PMID21750686.
- ^Starheim KK, Gevaert K, Arnesen T (April 2012). "Protein N-terminal acetyltransferases: when the start matters".Trends in Biochemical Sciences.37(4): 152–61.doi:10.1016/j.tibs.2012.02.003.PMID22405572.
- ^abcdeLonard DM, O'Malley BW (October 2012)."Nuclear receptor coregulators: modulators of pathology and therapeutic targets".Nature Reviews. Endocrinology.8(10): 598–604.doi:10.1038/nrendo.2012.100.PMC3564250.PMID22733267.
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- ^Berk A, Zipursky SL, Matsudaira PT, Baltimore D, Darnell J (2000). Lodish HF (ed.).Molecular Cell Biology(4th ed.). New York: W.H. Freeman.ISBN978-0-7167-3136-8.OCLC41266312.
- ^Becnel LB, Darlington YF, Orechsner S, Easton-Marks J, Watkins CA, McOwiti A, Kankanamge WH, Dehart M, Silva CM. "CBP".NURSA Molecules.doi:10.1621/8egsudafco.
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- ^Tien JC, Xu J (November 2012)."Steroid receptor coactivator-3 as a potential molecular target for cancer therapy".Expert Opinion on Therapeutic Targets.16(11): 1085–96.doi:10.1517/14728222.2012.718330.PMC3640986.PMID22924430.
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External links
[edit]- Nuclear Receptor Signalling Atlas(NIH-funded research consortium and database; includes open-access PubMed-indexed journal,Nuclear Receptor Signaling)
- TcoF - Dragon database of transcription co-factors and transcription factor interacting proteins