Coactivator (genetics)

Some 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. 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. Histone acetyltransferase 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 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. 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. 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. Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts. HAT mediated histone acetylation is reversed using histone deacetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones. Corepression Many coactivators also function as corepressors under certain circumstances. 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). == Significance ==

Biological significance Transcriptional regulation is one of the most common ways for an organism to alter gene expression. The use of activation and coactivation allows for greater control over when, where and how much of a protein is produced. As drug targets Coactivators are promising targets for drug therapies in the treatment of cancer, metabolic disorder, cardiovascular disease and type 2 diabetes, along with many other disorders. 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. Because transcription factors control many different biological processes, they are ideal targets for drug therapy. 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. 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. == Known coactivators ==

To date there are more than 300 known coregulators. • ARA54 targets androgen receptors • ATXN7L3 targets several members of the nuclear receptor superfamily • BCL3 targets 9-cis retinoic acid receptor (RXR) • CBP targets many transcription factors • CDC25B targets steroid receptors • COPS5 targets several nuclear receptors • DDC targets androgen receptors • EP300 targets many transcription factors • KAT5 targets many nuclear receptors • KDM1A targets androgen receptors • Steroid receptor coactivator (SRC) family • NCOA1 targets several members of the nuclear receptor superfamily • NCOA2 targets several members of the nuclear receptor superfamily • NCOA3 targets several nuclear receptors and transcription factors • YAP targets transcription factors • WWTR1 targets transcription factors == See also ==