| 词条 | Coactivator (genetics) |
| 释义 |
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.[1] The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer.[2][3] Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene 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 have histone acetyltransferase (HAT) activity. HATs form large multiprotein complexes that weaken the association of histones to DNA by acetylating the N-terminal histone 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 living organisms, 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] MechanismSome coactivators indirectly regulate gene expression by binding to an activator and inducing a conformational change that then allows the activator to bind to the DNA enhancer or promoter sequence.[2][15][7] 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.[8] Histone acetyltransferaseNuclear DNA is normally wrapped tightly around histones, making it hard or impossible for the transcription machinery to access the DNA. This association is due primarily to the electrostatic attraction between the DNA and histones as the DNA phosphate backbone is negatively charged and histones are rich in lysine residues, which are positively charged.[9] The tight DNA-histone association prevents the transcription of DNA into RNA. Many coactivators have histone acetyltransferase (HAT) activity meaning that they can acetylate specific lysine residues on the N-terminal tails of histones.[4][10][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.[10][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] 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 deactetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones.[4][10][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][10] Examples of coactivators that display HAT activity include CARM1, CBP and EP300.[14][15] CorepressionMany coactivators also function as corepressors under certain circumstances.[5][8] Cofactors such as TAF1 and BTAF1 can 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).[8] SignificanceBiological significanceTranscriptional 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][10][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][10] Associated disordersMutations to coactivator genes leading to loss or gain of protein function have been linked to diseases and disorders such as birth defects, cancer (especially hormone dependent cancers), neurodevelopmental disorders and intellectual disability (ID), among many others.[17][5] Dysregulation leading to the over- or under-expression of coactivators can detrimentally interact with many drugs (especially anti-hormone drugs) and has been implicated in cancer, fertility issues and neurodevelopmental and neuropsychiatric disorders.[5] For a specific example, dysregulation of CREB-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 to Huntington's Disease, leukaemia, Rubinstein-Taybi syndrome, neurodevelopmental disorders and deficits of the immune system, hematopoiesis and skeletal muscle function.[14][18]As drug targetsCoactivators are promising targets for drug therapies in the treatment of cancer, metabolic disorder, cardiovascular disease and type 2 diabetes, along with many other disorders.[5][19] For example, the steroid receptor coactivator (SCR) NCOA3 is often overexpressed in breast 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 coactivatorsTo date there are more than 300 known coregulators.[15] Some examples of these coactivators include:[22]
See also
References1. ^1 2 3 4 5 {{cite book | title = Mechanisms in transcriptional regulation | last = Courey | first = Albert J. | name-list-format = vanc | date = 2008 | publisher = Blackwell | isbn = 978-1-4051-0370-1 | location = Malden, MA | pages = | oclc = 173367793 }} 2. ^1 2 {{cite web | url = https://www.nature.com/scitable/definition/transcription-factor-167 | title = General transcription factor / transcription factor | work = Learn Science at Scitable | access-date = 2017-11-29 }} 3. ^1 {{cite journal | vauthors = Pennacchio LA, Bickmore W, Dean A, Nobrega MA, Bejerano G | title = Enhancers: five essential questions | journal = Nature Reviews Genetics | volume = 14 | issue = 4 | pages = 288–95 | date = April 2013 | pmid = 23503198 | pmc = 4445073 | doi = 10.1038/nrg3458 }} 4. ^1 2 3 4 5 6 7 {{cite journal | vauthors = Brown CE, Lechner T, Howe L, Workman JL | title = The many HATs of transcription coactivators | journal = Trends in Biochemical Sciences | volume = 25 | issue = 1 | pages = 15–9 | date = January 2000 | pmid = 10637607 | doi = 10.1016/S0968-0004(99)01516-9 }} 5. ^1 2 3 4 {{cite book | title = NR coregulators and human diseases | last1 = Kumar | first1 = Rakesh | last2 = O'Malley | first2 = Bert W. | name-list-format = vanc | publisher = World Scientific | year = 2008 | isbn = 978-981-270-536-5 | location=Hackensack, N.J. | pages = | oclc = 261137374 }} 6. ^{{cite journal | vauthors = Vosnakis N, Koch M, Scheer E, Kessler P, Mély Y, Didier P, Tora L | title = Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription | journal = The EMBO Journal | volume = 36 | issue = 18 | pages = 2710–2725 | date = September 2017 | pmid = 28724529 | doi = 10.15252/embj.201696035 | pmc=5599802}} 7. ^{{cite journal | vauthors = Scholes NS, Weinzierl RO | title = Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions | journal = PLoS Computational Biology | volume = 12 | issue = 5 | pages = e1004935 | date = May 2016 | pmid = 27175900 | doi = 10.1371/journal.pcbi.1004935 | pmc=4866707}} 8. ^1 2 {{cite journal | vauthors = Thomas MC, Chiang CM | title = The general transcription machinery and general cofactors | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 41 | issue = 3 | pages = 105–78 | date = May 2006 | pmid = 16858867 | doi = 10.1080/10409230600648736 | citeseerx = 10.1.1.376.5724 }} 9. ^{{cite journal|last=Decher|first=Gero|date=1997-08-29|title=Fuzzy Nanoassemblies: Toward Layered Polymeric Multicomposites|journal=Science|language=en|volume=277|issue=5330|pages=1232–1237|doi=10.1126/science.277.5330.1232|issn=0036-8075}} 10. ^1 2 3 4 5 6 {{cite journal | vauthors = Spiegelman BM, Heinrich R | title = Biological control through regulated transcriptional coactivators | journal = Cell | volume = 119 | issue = 2 | pages = 157–67 | date = October 2004 | pmid = 15479634 | doi = 10.1016/j.cell.2004.09.037 }} 11. ^1 2 3 4 {{cite journal | vauthors = Hermanson O, Glass CK, Rosenfeld MG | title = Nuclear receptor coregulators: multiple modes of modification | journal = Trends in Endocrinology and Metabolism | volume = 13 | issue = 2 | pages = 55–60 | year = 2002 | pmid = 11854019 | doi = 10.1016/s1043-2760(01)00527-6 }} 12. ^1 {{cite journal | vauthors = Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T | title = NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation | journal = PLoS Genetics | volume = 7 | issue = 7 | pages = e1002169 | date = July 2011 | pmid = 21750686 | pmc = 3131286 | doi = 10.1371/journal.pgen.1002169 }} 13. ^{{cite journal | vauthors = Starheim KK, Gevaert K, Arnesen T | title = Protein N-terminal acetyltransferases: when the start matters | journal = Trends in Biochemical Sciences | volume = 37 | issue = 4 | pages = 152–61 | date = April 2012 | pmid = 22405572 | doi = 10.1016/j.tibs.2012.02.003 }} 14. ^1 2 3 4 {{cite journal | vauthors = Lonard DM, O'Malley BW | title = Nuclear receptor coregulators: modulators of pathology and therapeutic targets | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 10 | pages = 598–604 | date = October 2012 | pmid = 22733267 | doi = 10.1038/nrendo.2012.100 | pmc=3564250}} 15. ^1 2 3 {{cite journal | vauthors = Hsia EY, Goodson ML, Zou JX, Privalsky ML, Chen HW | title = Nuclear receptor coregulators as a new paradigm for therapeutic targeting | journal = Advanced Drug Delivery Reviews | volume = 62 | issue = 13 | pages = 1227–37 | date = October 2010 | pmid = 20933027 | doi = 10.1016/j.addr.2010.09.016 | pmc=5004779}} 16. ^1 {{cite web | url = https://www.nature.com/scitable/definition/enhancer-163 | title = Enhancer | work = Learn Science at Scitable | access-date=2017-11-29 }} 17. ^{{cite book | title = Molecular Cell Biology | date = 2000 | publisher = W.H. Freeman | first1 = Arnold | last1 = Berk | first2 = S. Lawrence | last2 = Zipursky | first3 = Paul T. | last3 = Matsudaira | first4 = David | last4 = Baltimore | first5 = James | last5 = Darnell | editor-first1 = Harvey F. | editor-last1 = Lodish | name-list-format = vanc | isbn = 978-0-7167-3136-8 | edition = 4th | location = New York | oclc = 41266312 }} 18. ^{{cite journal | last = Becnel | first = LB | last2 = Darlington | first2 = YF | last3 = Orechsner | first3 = S | last4 = Easton-Marks | first4 = J | last5 = Watkins | first5 = CA | last6 = McOwiti | first6 = A | last7 = Kankanamge | first7 = WH | last8 = Dehart | first8 = M | last9 = Silva | first9 = CM | name-list-format = vanc | title = CBP | journal = NURSA Molecules | doi = 10.1621/8egsudafco }} 19. ^{{cite web | url = https://courses.washington.edu/conj/bess/nuclear/nuclear.htm|title=Nuclear Receptors | website=courses.washington.edu | access-date = 2017-11-29 }} 20. ^{{cite journal | vauthors = Tien JC, Xu J | title = Steroid receptor coactivator-3 as a potential molecular target for cancer therapy | journal = Expert Opinion on Therapeutic Targets | volume = 16 | issue = 11 | pages = 1085–96 | date = November 2012 | pmid = 22924430 | doi = 10.1517/14728222.2012.718330 | pmc=3640986}} 21. ^{{cite journal | vauthors = Sladek FM | title = Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas | journal = Expert Opinion on Therapeutic Targets | volume = 7 | issue = 5 | pages = 679–84 | date = October 2003 | pmid = 14498828 | doi = 10.1517/14728222.7.5.679 }} 22. ^{{cite web|url=https://nursa.org/nursa/molecules/index.jsf|title=NURSA - Molecules|website=nursa.org|language=en|access-date=2017-11-30}} External links
4 : Gene expression|Molecular genetics|Proteins|Transcription coregulators |
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