A corepressor is a protein that controls gene activity within cells. It helps turn off, or repress, specific genes. One can imagine a corepressor as an assistant to a dimmer switch, helping to lower the light intensity without directly operating the main switch itself. These proteins are important for proper cellular function, ensuring genes are silent when needed.
The Mechanism of Gene Silencing
Corepressors are brought to specific locations on the DNA by other proteins known as repressors, which recognize and bind to particular DNA sequences. Once recruited, the corepressor functions as a scaffold, attracting and assembling a team of other enzymes. An example of these enzymes is Histone Deacetylases (HDACs).
HDACs perform a specific chemical modification: they remove acetyl groups from histone proteins. Histones are like spools around which DNA is wound, forming a structure called chromatin. The removal of acetyl groups by HDACs causes the chromatin to become more tightly packed and condensed. This increased compaction physically restricts access to the DNA.
When chromatin condenses, the machinery responsible for gene transcription, which reads the DNA to create proteins, cannot reach the gene. The inability of this machinery to access the DNA results in the gene being silenced, preventing its instructions from being read and its protein from being made.
Distinguishing Corepressors From Repressors
A repressor protein directly recognizes and binds to specific DNA sequences, acting as an “address finder” to direct silencing machinery. Without the repressor, the corepressor would not know where to act.
A corepressor, in contrast, does not bind directly to the DNA. It binds to the repressor protein to execute the silencing action. This action often involves recruiting additional proteins, such as HDACs, to modify the chromatin structure.
Biological Significance in Cellular Processes
Precise control over gene repression, often mediated by corepressors, is important for an organism’s proper functioning and health. This mechanism is important during embryonic development, where cells specialize. For instance, corepressors ensure genes for one cell type (e.g., neuron) are turned off when a cell is destined to become another (e.g., muscle cell). This selective silencing allows for distinct tissues and organs.
Corepressors also play a role in regulating ongoing cellular processes, such as metabolism. They fine-tune genes involved in nutrient and energy processing. They also regulate daily circadian rhythms, the body’s internal clocks governing sleep-wake cycles. These rhythms require precise gene activation and deactivation, a process involving corepressors.
Implications in Disease and Therapeutics
Malfunctions in corepressor activity are linked to various human diseases. In cancer, for example, corepressor failure to silence growth-promoting genes can lead to uncontrolled cell division and tumor formation. Disruptions have also been implicated in metabolic disorders, impairing nutrient processing, and in certain inflammatory diseases.
Due to their involvement in disease pathways, corepressors and associated enzymes like HDACs are attractive drug targets. Scientists are investigating ways to modulate their activity. For instance, HDAC inhibitors are used in certain cancers. These inhibitors prevent HDACs from removing acetyl groups, reactivating improperly silenced tumor-suppressing genes and counteracting uncontrolled cell growth.