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RNA Rules the Ribosome

16 February 2004 (All day)
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Small RNA molecules have electrified scientists in recent years with their newly discovered roles in controlling gene expression. The surprises are apparently far from over: Another kind of RNA can detect levels of small molecules that help a cell run smoothly, and switch genes on or off depending on the cell's needs.

Molecular biologist Ronald Breaker of Yale University and his colleagues unearthed these multitalented RNA molecules--a class he calls riboswitches--after wading through decades of scientific literature and puzzling over a handful of unsolved mysteries. Small molecules called metabolites mediate a cell's survival, and metabolite production is fine-tuned by genes that indirectly sense metabolite levels. It had long been assumed that specific proteins bind to a metabolite and trigger expression or repression of genes. But Breaker uncovered seven cases in bacteria, some as old as 30 years, in which frustrated scientists searched in vain for that key protein. There was a reason they couldn't find it, he says: The mystery protein was actually messenger RNA (mRNA). It normally carts the information from DNA to a cell's ribosome, where it's translated into a protein.

Riboswitches--so named because they meddle with the ribosome--are portions of specific mRNAs that bind to a metabolite. That changes the shape of the mRNA and switches a gene off, or occasionally on. "It was right in front of you in the literature for 20 or 30 years," says Thomas Tuschl, an RNA researcher at Rockefeller University in New York City. But until Breaker, no one had looked.

At the meeting, Breaker reported on his eighth bacterial riboswitch, which will appear in Nature. The switch mediates levels of glucosamine, a key sugar that helps bacteria build their cell wall. Unlike the previous seven (those unsolved mysteries from the past), the new riboswitch is also a ribozyme, a scissors-like molecule that can cut up RNA and uses this ability to control gene expression. When glucosamine reaches high levels in the cell, the metabolite binds to mRNA and induces the mRNA to cut itself. That prompts a plunge in gene expression because DNA's message to churn out glucosamine can no longer be transcribed. Mysteriously, the mRNA gets sliced at a site that doesn't code for DNA, but that still manages to disrupt DNA expression. "We don't know why" that happens, says Breaker. "It's a little eerie," notes Sean Eddy, a computational biologist at Washington University in St. Louis, Missouri.

Still, it's clear that "bacteria are loaded" with riboswitches, says Breaker. He's confirmed two more that aren't yet published and has 10 other candidates. The switches have also been found in fungi and plants, and Breaker is planning to start hunting for them soon in animals.

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