Acoactivator is a type oftranscriptional coregulator that binds to anactivator (atranscription factor) to increase the rate oftranscription of agene or set of genes.[1] The activator contains aDNA binding domain that binds either to a DNApromoter site or a specific DNAregulatory sequence called 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 ofhistones to DNA byacetylating theN-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 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]
Some coactivators indirectly regulate gene expression by binding to an activator and inducing aconformational change that 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]
Nuclear 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 theelectrostatic attraction between the DNA and histones as the DNAphosphate backbone 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 specificlysine residues 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]
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,CBP andEP300.[14][15]
Many coactivators also function ascorepressors under certain circumstances.[5][9] Cofactors such asTAF1 andBTAF1 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).[9]
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]
Mutations to 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 disorders andintellectual disability (ID), among many others.[17][5] Dysregulation leading to the over- or under-expression of coactivators can detrimentally interact with many drugs (especiallyanti-hormone drugs) and has been implicated in cancer,fertility issues 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,hematopoiesis andskeletal muscle function.[14][18]
Coactivators are promising targets for drug therapies in the treatment of cancer,metabolic disorder,cardiovascular disease andtype 2 diabetes, along with many other disorders.[5][19] For example, the steroid receptor coactivator (SCR)NCOA3 is 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]
To date there are more than 300 known coregulators.[15] Some examples of these coactivators include:[22]
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