10.10: Eukaryotic Transcription Inhibitors
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA binding domain and a repressor domain. Repressor domains of transcription inhibitors can bind to other proteins, such as basal transcriptional regulators, activators, co-activators, and co-repressors. Repression domains can be vaguely categorized on the basis of their constituent amino acids, such as alanine -rich domains, glutamine rich domains, and proline rich domains. They can also be categorized as acidic or basic domains, and as hydrophilic or hydrophobic. These domains are often interchangeable and different repressor domains can associate with the same DNA binding domain.
Eukaryotic transcription inhibitors can carry out their function through three major mechanisms – inhibiting DNA binding, blocking activation, and gene silencing.
Inhibition of DNA binding either prevents the activator from binding to the promoter or enhancer site, or it can prevent the transcription initiation complex from binding the transcription start site or the TATA box. This could occur either through the binding of the inhibitor to the regulatory or start site or through the association of the inhibitory domain with activators, co-activators, or proteins involved in the transcription machinery. For example in humans, the transcription inhibitor NF-E binds to the CCAAT box of the fetal γ-globin gene and inhibits the binding of the activator CP1.
Blocking activation prevents the signal from a transcription activator bound to a promoter or enhancer from reaching the transcription start site. This can occur when an inhibitor binds to a site adjacent to the promoter or enhancer, like in the regulation of c-myc where the inhibitor myc-PRF binds next to the promoter. It can also occur through the inhibitor binding to a DNA bound activator. This type of repression occurs when the inhibitor GAL80 in yeast binds to the activator GAL4 when it is bound to the promoter.
Gene silencing occurs when the inhibitor either locks or disorganizes the transcription initiation complex by simultaneously binding to one of the proteins that constitute the machinery and to a site on the DNA near the transcription start site, thereby anchoring the transcription machinery. For example, in yeasts the inhibitor α-2 inactivates the mating type a-specific genes by binding as a dimer to the activator GRM and to DNA sequences bordering the binding site of GRM.