Gene Regulation Is Necessary?
By switching genes off when they are not needed, cells can prevent resources from being wasted. There should be natural selection favoring the ability to switch genes on and off.
Complex multicellular organisms are produced by cells that switch genes on and off during development.
A typical human cell normally expresses about 3% to 5% of its genes at any given time.
Cancer results from genes that do not turn off properly. Cancer cells have lost their ability to regulate mitosis, resulting in uncontrolled cell division.
Much of our understanding of gene control comes from studies of prokaryotes. The discussion below shows how gene expression is regulated by controlling transcription.
Operons contain groups of genes that are regulated together. The advantage is that a group of genes whose products are all needed for a common function, can be transcribed together and a single signal can be used to control whether the genes are actively transcribed or not.
Typically, an operon contains a promoter, genes to be transcribed, and an operator. The operator is a region of DNA within the promoter or between the promoter and the genes to be transcribed. When inhibitors are bound to the operator, RNA polymerase cannot transcribe the genes.
Operons are found mostly in prokaryotes
The lac operon
E. coli (the common intestinal bacterium) prefers glucose over lactose as a source of food. If glucose and lactose are both present, it uses glucose; enzymes needed to digest lactose are not produced. If glucose is absent and lactose is present, it activates genes that code for the production of lactose-digesting enzymes.
In the diagrams below, the structural genes needed to synthesize lactose-digesting enzymes (Z, Y, and A) are inactive because a repressor is attached to the promoter region of DNA, preventing transcription. When the repressor protein is bound to the DNA, RNA polymerase cannot bind to the DNA. The protein must be removed before the genes can be transcribed.
Below: Allolactose, an isomer of lactose, binds with the repressor protein inactivating it. This enables RNA polymerase to bind to the promoter but transcription proceeds at a slow rate. As a result, glucose is used as the primary food source.
If the level of glucose in the cell declines, the level of cAMP increases.
Cyclic AMP binds to CAP (catabolite activator protein) and this complex binds to the promoter region, enhancing the attachment of RNA polymerase. As discussed above, the repressor does not interfere due to the presence of lactose.
Transcription of the genes, therefore requires glucose to be absent or at very low levels and lactose to be present.
The lac operon is an inducible operon that uses both negative and positive control. It is inducible because the structural genes are normally inactive but the presence of lactose induces them to become active. The repressor acts as a negative control mechanism because an active repressor prevents transcription. The activated CAP protein acts as a positive control mechanism because it promotes transcription. Negative control mechanisms thus inhibit transcription and positive control mechanisms enhance transcription.
Repressible operons are the opposite of inducible operons. Transcription occurs continuously and the repressor protein must be activated to stop transcription.
Tryptophan is an amino acid needed by E. coli and the genes that code for proteins that produce tryptophan are continuously transcribed as shown below.
If tryptophan is present in the environment, however, E. coli does not need to synthesize it and the tryptophan-synthesizing genes should be turned off. This occurs when tryptophan binds with the repressor protein, activating it. Unlike the repressor discussed with the lac operon, this repressor will not bind to the DNA unless it is activated by binding with tryptophan.. Tryptophan is therefore a corepressor.
The trp operon is a repressible operon that uses negative control.It is repressible because the structural genes are normally active but are repressed when tryptophan is present. It is negative control because the presence of an active repressor prevents transcription. Notice that both the lac operon (discussed earlier) and the trp operon use negative control.
The table below summarizes negative regulation of operons.
|Active||Inactive (inhibits |
Negative Feedback Inhibition
In addition to genetic regulation, tryptophan can inhibit the first enzyme in the synthesis pathway. This is an example of feedback inhibition. The presence of high levels of tryptophan inhibits the activity of the enzyme as shown in the biosynthesis pathway below.
The trp and lac operons discussed above are examples of negative control because a repressor blocks transcription. In one case (lac operon) the repressor is active and prevents transcription. In the other case (trp) the repressor is inactive and must be activated to prevent transcription.
Positive control mechanisms require the presence of an activator protein before RNA polymerase will bind. The activator protein itself must be activated by binding to an inducer molecule. Once activated, the activator binds to DNA and enables the binding of RNA polymerase.
Genes which code for enzymes necessary for the digestion of maltose are regulated by this mechanism. Maltose acts as the inducer, binding to an activator and then to mRNA. The activator bound to mRNA stimulates the binding of RNA polymerase.
The lac operon discussed earlier as an example of negative control and is also an example of positive control. The cell normally uses glucose as a carbon source. When the level of glucose declines, the level of a signaling molecule called cyclic AMP (cAMP) increases. Cyclic AMP binds to a protein called CAP (catabolic activator protein) which then binds to the promoter region, causing transcription to occur. Reduced glucose, therefore, promotes the transcription of the lac Z, Y, and A genes. However, because the lac operon is inducible, lactose must be present.
By having both positive and negative control operating at the same time, the structural genes in the lac operon are not active unless the level of glucose is reduced and lactose is available.