Gene regulation in viruses

SIGNIFICANCE: Gene regulation in viruses typically resembles that of the hosts they infect. Because viruses are not alive and are incapable of self-replication, gene regulation at the time of initial infection depends on their host’s control systems. Once infection is established, regulation is generally mediated by gene products of the virus’s own DNA or RNA.

General Aspects of Regulation

Regardless of the type of organism, DNA is the genetic material that allows species to survive and pass their traits to the next generation. Genes are encoded, along with control sequences that the cell uses to control expression of their associated genes. Although details of these control sequences vary between prokaryotes and eukaryotes, they still function in similar ways. One element common to all genes is a promoter, a sequence that acts as the binding site for RNA polymerase, the that transcribes the gene into RNA so it can be translated into a protein product. Other control sequences, if present, simply help control whether or not can bind to the promoter, or they increase or decrease the strength of RNA polymerase binding. These secondary control sequences, therefore, act as switches for turning on or off their associated genes. Some may also act like a dimmer switch, increasing or decreasing the rate at which a gene is expressed.

Viruses are incapable of self-replication and must rely on the host cells they infect. In order to replicate successfully, a virus must be compatible with the host’s cell biochemistry and gene-regulation systems. When a virus first enters a host cell, its genes are regulated by the host. Thus, viral promoters and other control elements must be compatible with those of the host. The control elements associated with promoters in prokaryotes are called operators. An operator represents a site where a regulatory protein (a product of yet another gene) can bind and either increase or decrease the ability of RNA polymerase to bind to the of its associated gene or group of genes.

Eukaryotic systems (cells of plants and animals) are more complex and involve a number of proteins called transcription factors, which bind to or near the promoter and assist RNA polymerase binding. There are also proteins, which bind to other control sequences somewhere upstream from the gene they influence. Because of this greater complexity, viruses that infect eukaryotic cells are also more genetically complex than are viruses infecting prokaryotes.

Viral Genomes

All cells, including bacteria, are subject to infection by parasitic elements such as viruses. Viruses which specifically infect bacteria are known as bacteriophages, from the Greek phagos, “to eat.” The genetic information in viruses may consist of either RNA or DNA. All forms of viruses contain one or the other, but never both. Regardless of the type of genetic material, gene regulation does have certain features in common.

The size of the viral genome determines the number of potential genes that can be encoded. Among the smallest of the animal viruses are the hepadnaviruses, including hepatitis B virus, the DNA of which consists of some 3 kilobase pairs (3 kbp, or 3,000 base pairs), enough to encode approximately seven proteins. The largest known viruses are the poxviruses, consisting of 200-300 kbp, enough to encode several hundred proteins. Lambda is approximately average in size, with a DNA genome of 48 kbp, enough to encode approximately fifty genes.

Lambda as a Model System: The Lytic Cycle

Following infection of the bacterial host, most bacteriophages replicate, releasing progeny as the cell falls apart, or lyses. Lambda phage is unusual in that, while it can complete a lytic cycle, it is also capable of a nonproductive infection: Following infection, the viral genome integrates into the host chromosome, becoming a prophage in a process known as lysogeny. Such phages are known as temperate viruses.

Most viruses, including lambda, exhibit a temporal control of regulation: gene expression is sequential. Three classes of proteins are produced, classified based on when after infection they are expressed. “Immediate early” genes are expressed immediately after infection, generally using host machinery and enzymes. “Early” genes are expressed at a later time and generally require proteins expressed from early genes. “Late” genes are expressed following genome of the virus. The various temporal classes of gene products may also be referred to as lambda, beta, and gamma proteins.

The lytic cycle of lambda represents a prototype of temporal control. Lambda immediate early begins following infection of the host cell, Escherichia coli. Host cell enzymes catalyze the process. Transcription of lambda DNA begins at a site called a promoter, a region recognized by the host RNA polymerase, which catalyzes transcription. Lambda DNA is circular after entering the cell, and two promoters are recognized: One regulates transcription in a leftward direction (PL), while the other regulates transcription from the opposite strand in a rightward transcription (PR).

Among the immediate early genes expressed is one encoding the N protein, expression of which is under the control of PL. Generally, transcription occurs through a set of genes and is terminated at a specific point. The N protein is an example of an antiterminator, a protein that allows “read-through” of the stop signal for transcription and expression of additional genes. A second protein is encoded by the cro gene, the product of which plays a vital role in determining whether the infection is lytic or becomes lysogenic. Cro gene expression is controlled through PR, as are several “early class” genes which regulate viral (O and P genes), synthesis (cII), and early gene expression (Q gene).

Both the cro and Q proteins are involved in regulating “late” genes, those expressed following DNA replication. Like the N protein, the Q protein is an antiterminator. Late gene products include those that become the structural proteins of the viral capsid. Other late proteins cause cell lysis, releasing progeny phage particles from the cell. The entire process is completed in approximately thirty minutes.

Lambda: The Lysogenic Cycle

Lambda is among those bacterial viruses that can also carry out lysogeny, a nonlytic infection in which the virus integrates within the host chromosome. Lysogeny is dependent on the interaction between two gene products: the repressor, a product of the cI gene, and the cro protein.

The cII protein, an early gene product, activates the expression of cI, the gene that encodes the repressor. At this point in the cycle, it becomes a race (literally) between the activity of the repressor and the cro protein. Each has affinity for the operator regions (OL and OR) which control access to the respective promoters, PL and PR. If the repressor binds the operator regions before the cro protein, access to these sites by RNA polymerase is blocked, and the virus enters a lysogenic state. If the cro product binds first, repressor action is blocked, and the virus continues in a lytic cycle.

Lambda can remain in for an indefinite length of time. Because it is integrated with the host’s genome, every time the host reproduces, lambda is also reproduced. Lambda typically remains in the lysogenic phase, unless its host gets into difficulty. For example, if the host is “heat shocked,” it produces heat shock proteins that inadvertently destroy the lambda repressor protein. Without the repressor protein to block expression of the early genes, lambda enters the lytic phase. This switch to the lytic phase allows lambda to reproduce and leave its host before it is potentially destroyed with the host.

Regulation in Other Viral Systems

While lambda is unusual among the complex bacteriophages in carrying out both lytic and lysogenic cycles, regulation among other viruses, including those which infect animals, has certain features in common. Most viruses exhibit a form of temporal control. Regulation in T_even infection (T2, T4, or T6) is accomplished by altering the specificity of the RNA polymerase β, resulting in the recognition of alternate promoters at different times after infection. Bacteriophage T7 accomplishes the same task by encoding an entirely new polymerase among its own genes.

The complexity of animal viruses varies significantly; the greater the coding capacity, the more variability in regulation. Some animal viruses, such as the influenza viruses, encode different proteins on unique segments of genetic material, in this case RNA. DNA viruses such as the human herpesviruses (HHV) or poxviruses utilize the same form of temporal control as described above. In place of antiterminators, products of each time frame regulate subsequent gene expression. In some cases, unique polymerase enzymes encoded by the virus carry out transcription of these genes.

Despite their apparent complexity, viruses make useful models in understanding gene expression in general. Control elements resembling operators and promoters are universal among living cells. In addition, an understanding of regulation unique to certain classes of viruses, such as expression of new enzymes, provides a potential target for novel treatments.

Key Terms

• bacteriophagegeneral term for a virus that infects bacteria
• lambda(λ) phagea virus that infects bacteria and then makes multiple copies of itself by taking over the infected bacterium’s cellular machinery
• lysogenya process whereby a virus integrates into a host chromosome as a result of nonlytic, nonproductive, infection
• operatora sequence of DNA adjacent to (and usually overlapping) the promoter site, where a regulatory protein can bind and either increase or decrease the ability of RNA polymerase to bind to the promoter
• promotera sequence of DNA to which the gene expression enzyme (RNA polymerase) attaches to begin transcription of the genes of an operon

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