Transcriptional coactivator (Coactivator)

Transcriptional coactivators are a diverse class of proteins that increase the frequency of gene transcription by acting as bridges between sequence-specific DNA-binding transcription factors and the basal transcription machinery, including RNA polymerase II [1]. Unlike transcription factors, they generally lack the ability to bind DNA directly and instead exert their effects through protein-protein interactions or by modifying chromatin structure via enzymatic activities like histone acetylation [2][3]. Key examples include the p300/CBP family, the Mediator complex, and the bromodomain and extra-terminal (BET) protein family [4]. In various diseases, particularly cancer, these coactivators are frequently overexpressed or mutated, leading to the sustained activation of oncogenic pathways such as MYC or Hippo/YAP signaling [5]. Consequently, they have emerged as high-value therapeutic targets, though their widespread involvement in normal cellular homeostasis presents significant challenges regarding systemic toxicity and achieving a narrow therapeutic window [6][8]. Sources: [1] NIH/NCBI Bookshelf (NBK21745); [2] Nature Reviews Molecular Cell Biology (nrm1839); [3] PubMed (11459971); [4] Nature Reviews Cancer (nrc3014); [5] Nature Reviews Drug Discovery (nrd.2017.119); [6] PubMed (22492576); [7] PubMed (17563065); [8] Nature Reviews Drug Discovery (24855266); [9] ClinicalTrials.gov (NCT03568331); [10] PubMed (22442020).

Other names

Transcription coactivatorCoregulatorTranscriptional coregulatorTranscriptional adapter

Transcriptional coactivators are targeted by small molecules that disrupt protein-protein interactions (e.g., inhibiting bromodomain-histone binding), inhibit enzymatic activities such as histone acetyltransferase (HAT) function, or induce targeted protein degradation (PROTACs), thereby preventing the assembly of the transcription initiation complex at specific oncogenic or inflammatory gene promoters [1][8].