After his computational studies suggested that RNA regulates gene expression in riboflavin biosynthesis, Mikhail Gelfand began using riboswitches to study evolution.

"We were engineering riboswitches long before we discovered them in nature," Breaker says. "There was no evidence at the time that these switches were still in existence. But, it was so easy to build them that we thought there was no way that nature had forgotten this technology."

With that thought, Breaker decided to search for ancient RNA switches in modern bacteria.

While Breaker's group was building RNA sensors, Mikhail S. Gelfand, then at the Research Institute of Genetics and Selection of Industrial Microorganisms in Moscow, his student Alexey Vitreschak, and biologist Yuri Kozlov were probing how bacteria regulate production of riboflavin, one of the B vitamins the body uses to metabolize fats, carbohydrates, and proteins.

They knew the vitamin derivative flavin mononucleotide (FMN) stopped expression of certain genes involved in riboflavin biosynthesis. "But, the biologists were saying that there wasn't a protein involved. It was about that same time that people started writing about RNA aptamers," says Gelfand, now an HHMI international research scholar at the A.A. Kharkevich Institute for Information Transmission Problems in Moscow.

By examining the genomes of diverse bacterial species, the group found an unusual similarity in a section of the messenger RNA (mRNA) called the 5 prime untranslated region (5' UTR). "These very different species had a region of similarity in the 5' UTR that was completely unexpected," Gelfand says.

Their computational work revealed that the 5' UTR of the RNA could fold into a cloverleaf structure that was highly conserved among species. He speculated that this structure bound FMN. What's more, Vitreschak and Gelfand discovered that the RNA could form another structure that would stop the transcription of mRNA dead in its tracks and suggested that the RNA was regulating gene expression.

Normally, when a cell needs to shut down production of a protein from an mRNA, regulatory proteins jump onto the 5' UTR—the real estate on the mRNA in front of the section coding for protein. That gums up the works, stopping the ribosome from making the protein.

Back in Connecticut, Breaker began looking for examples of genes that are sensitive to the amount of a vital nutrient, but for which scientists had been unable to find a regulatory protein that orchestrates response to the level of that nutrient. If there was no protein, maybe there was a riboswitch.

Photo: Paul Fetters

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