By Dean Haycock

Special To BioWorld Today

The red clover necrotic mosaic virus (RCNMV) is obscure compared to headline grabbers like HIV and Ebola. It is a plant virus and not a very important one.

It makes a good model system, though, because it is genetically simple. Its genome consists of only two single-stranded ribonucleic acids (RNAs), and the way these two RNA components interact makes the RCNMV quite newsworthy.

Whereas other microbes, plants and animals use proteins to control gene expression, the RCNMV uses RNA. Its unprecedented use of RNA to control the expression of genes could have significant implications for several areas of biology, ranging from biotechnology to the study of the origin of life.

RNA is a complex molecule best known for its role in protein synthesis. It replaces DNA as the source of genetic information in some viruses such as RCNV. RNA comes in different forms with different functions. There are messenger RNAs, transfer RNAs and ribosomal RNAs, which together allow DNA's message to be transcribed, translated and converted into proteins.

In addition to the three main types of RNA, several other small RNA molecules and molecules made of RNA and protein, called ribonucleoproteins, are found in cells. Some RNA can even act as biological catalysts — a job previously attributed exclusively to proteins. Other RNAs regulate cell division and differentiation.

Despite this extensive repertoire of biological functions no RNA molecule has ever been shown to control gene expression, another role thought to be limited to proteins.

The first evidence that an RNA-RNA interaction can turn on a gene appears in the Aug. 7 issue of Science. Steven Lommel, professor of plant pathology at North Carolina State University, in Raleigh, N.C., and his colleagues describe the phenomenon in their article "RNA-mediated trans-activation of transcription from a viral RNA."

The genome of the RCNMV consists of RNA-1 and RNA-2. RNA-1 encodes instructions for making the virus's coat protein and for making an enzyme called RNA polymerase. RNA-2 encodes information for making a "movement" protein, which the virus uses to move from an infected cell into a healthy one.

The North Carolina researchers discovered that specific base-pairs, which are chemical building blocks, of the two RNAs can interact in the virus. This interaction initiates transcription, the transfer of genetic information from a genetic blueprint molecule. Before this discovery, transcription had always been attributed to protein regulators. It is not clear yet whether the interaction between the two RNAs requires the assistance of proteins.

"We are going to find out if there is indeed a protein involved or whether it is truly only an RNA-RNA interaction," Lommel said.

The work has potential biotechnology applications. RNA-RNA interactions might be used, for example, to temporally control gene expression in plants. Lommel offers an example in which farmers use corn or wheat that contains a foreign gene. Depending on the economic outlook, farmers could decide to harvest the crop for grain or — by super-infecting the plants with elements of the RNA system — turn on the gene to direct the plants' growth for other purposes.

RNA: Prime Player In Life's Origin

The University of North Carolina has submitted a patent application that would cover the elements of the virus's unique gene transcription system. Since the present paper is based on genetic proof, future work in Lommel's lab will include gathering physical evidence of the RNA-RNA interaction.

Lommel is realistic about the biological significance of the finding. "Honestly speaking, this could be such a bizarre and obscure phenomenon that it could turn out to be an important regulatory mechanism only in a small group of plant viruses," he said. "If that were the case, it would be an interesting observation, but it would not be significant biologically."

He adds, however, that this mechanism might be more widely used in nature. In situations where it is not clear how genes are regulated, Lommel suggests scientists now consider the activity of some other RNA transcripts binding to the gene promoter region to regulate gene expression.

Another area that may be influenced by the new RCNMV data is the study of the origin of life. As scientists learn that RNA can perform more functions previously ascribed only to proteins, it appears more likely that RNA was perhaps the prime player in the evolution of life. This proposed central role for the nucleic acid is reflected in a theory referred to as the "RNA World."

The origin of life depended on the appearance of molecules that could replicate. RNA has a prime role in this theory because it has specific catalytic surfaces and the ability to form complementary molecules through base pairing. After much trial and error, according to the theory, a small RNA molecule appeared that could catalyze the formation of copies of itself. Other RNA molecules presumably benefited from natural selection as they aided the replication of the reproducing RNA.

Replaced By DNA As Genetic Blueprint

Eventually, a sophisticated system comprising RNA catalysts evolved. Later, a mechanism for synthesizing proteins appeared. Finally, DNA replaced RNA as nature's favorite genetic blueprint because it is more stable. In most cases, RNA gave up its prime role as repository of genetic information to DNA and lost the ability to reproduce. At this advanced stage of evolution, the elements of the central dogma of biology took shape: DNA to RNA to protein.

"Our data is somewhat compelling because [other researchers] have now shown that RNA has enzymatic activity," Lommel said. "RNA also encodes genetic information, so it can maintain or perpetuate a genetic code if it could replicate. Basically, we have shown that RNA can undertake a new activity, that is, regulate itself."

The finding that the RCNMV uses an RNA-RNA interaction to initiate genetic transcription provides important support for the theory that life began in an RNA world.

"RNA can bend back on itself and turn itself on or off," Lommel said. "Now, we have a way in which RNA can autoregulate its other activities, without necessarily requiring a protein. It does add to the idea that RNA can do a lot of things." *

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