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Gotta love those viruses

Infectious agents earn scientists' affection, says researcher Adam Geballe, who examines gene expression in CMV
Dr. Adam Geballe pipets samples of viral DNA for analysis.
Dr. Adam Geballe pipets samples of viral DNA for analysis. Viruses have proved to be excellent models for scientists who study gene regulation. Photo by Michelle Hruby

Viruses inflict the cough and congestion of the common cold and breed deadly epidemics like those of smallpox and AIDS.

Yet these microscopic packages of protein and genetic information are among scientists' best-loved tools.

With only a handful to a few hundred genes, viruses have helped to shed light on many diseases including cancer and have been indispensable for techniques like genetic engineering and gene therapy. A virus even claims rights as the first-ever organism whose genome was completely sequenced.

Their heyday in biology isn't over. For scientists who study how genes switch on and off, these infectious agents continue to fuel new discoveries, said Dr. Adam Geballe of the Human Biology Division.

"Viruses are great models for studying gene regulation," he said. "They've given us an enormous number of tools and insights-because the mechanisms viruses use for basic biological processes have implications for other systems, including human cells."

His ongoing studies on gene expression in cytomegalovirus (CMV), a pathogen notorious as a serious risk factor for bone-marrow transplant recipients, have already revealed related processes in human cells. What's more, Geballe's recent survey of the CMV genome sequence might even demonstrate that viruses serve as good role models for one of the most controversial problems in biology: determining the number of genes in the human genome.

More than 10 years ago, Geballe discovered an unusual form of gene regulation in CMV that his lab later found also affects HER-2/neu, a gene involved in many cases of human breast cancer. And, he said, there are likely to be other examples in cells from many different organisms.

Translation synthesis

Geballe's work focuses on the second phase in the pathway that enables cells to decode DNA instructions into proteins, the molecules that constitute the structural elements and working machinery of all cells. Known as translation, or protein synthesis, the process involves the step-by-step assembly of amino acids, the building blocks of proteins, into functional molecules whose composition is based on information contained in the DNA.

Translation follows a process called transcription, which converts DNA, primarily an information repository, into RNA, the messenger molecule that is actually interpreted into protein.

Although regulation of transcription may be the cell's preferred or at least best-studied mechanism for controlling gene expression, cells manipulate translation for some critical functions.

For example, many cells completely shut down translation after infection with a virus. Like an immune response, this blockade inhibits viral protein synthesis, foiling the pathogen's ability to reproduce, although clever viruses have ways to get around this obstacle.

Likewise, a similar translation shut-off at the earliest signs of cancer may help to halt abnormal cells in their tracks before they multiply. Not surprisingly, many advanced cancers have defects in this pathway.

Discovery of a gene

Geballe's studies on translation led to discovery of a CMV gene whose translation is controlled by a tiny stretch of DNA near the beginning of the gene. Called uORFs, for upstream open reading frames, these short genetic fragments possess all the right DNA sequences to undergo protein synthesis themselves, but their small size makes them suspect as functional genes. While most genes consist of thousands of the chemical building blocks known as bases that comprise DNA, a uORF may have fewer than 50.

Geballe, also an associate professor of medicine at the University of Washington and a physician specializing in infectious diseases, discovered that the small DNA fragment does indeed make a protein whose job is to interfere with the translation of its neighboring gene.

Why would an organism use such an intricate mechanism to control a gene?

In the case of the CMV gene, Geballe said, the answer isn't clear. But the observation that oncogenes, genes frequently mutated in cancer cells, also contain neighboring uORFs may provide some clues.

"Oncogene expression needs to be very tightly regulated in order to prevent cells from becoming cancerous," he said. "This layer of regulation may provide an extra measure of control. At this point, we don't know how many genes have these adjacent uORFs. It could be a lot more common than we think."

In fact, this may likely prove to be the case in CMV. Geballe recently took a close look at the DNA sequence of the CMV genome and concluded that ORFs (both uORFs, which lie "upstream"of genes as well as other small potentially translated DNA segments) may be widespread throughout the viral DNA.

"We reanalyzed the published CMV gene sequence, which has been predicted to contain 200 genes," he said. "By our analysis, which takes into account these small ORFs, it looks like there could be as many as 1600 genes. But whether these are ever actually translated into proteins or involved in translational regulation remains to be determined."

This re-analysis of this viral genome provides new food for thought for interpretation of the genomes of more complex organisms, including that of humans. The first inspection of the complete human DNA sequence, which involved "reading" the DNA letters for the clues that signal the start and stop of a gene, led scientists to believe that it contains about 30,000 to 50,000 genes.

Since this kind of assessment usually overlooks very small genes, "upon closer inspection, there may be many more genes than initially predicted," Geballe said.

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