Loophole found in genetic traffic laws

Altered molecule causes protein-making machinery to run stop signs

Biology’s rules may be full of exceptions, but a new discovery has uncovered a violation in a rule so fundamental that geneticists call it the central dogma.

The molecular equivalent of writing one RNA letter in a different font can change the way a cell’s protein-building machinery interprets the genetic code, Yitao Yu and John Karijolich of the University of Rochester in New York report in the June 16 Nature. They found that occasional conversions of a genetic letter found in RNA into a slightly different form can cause a cell’s protein-building machinery to roll right through a stop sign.

That might seem like a run-of-the-mill molecular traffic violation, but it results in an entirely different protein than the one encoded by DNA — a clear violation of the central dogma.

The central dogma holds that DNA is the repository for all genetic instructions in a cell. The tenet declares that those instructions are carefully transcribed into multiple messenger RNA, or mRNA, copies, which are then read in three-letter chunks called codons by cellular machinery called ribosomes. Ribosomes then convert the mRNA instructions into proteins.

Yu and Karijolich studied pseudouridine, a slightly different version of the RNA component uridine. The enzymes that copy DNA to RNA and vice versa can’t tell the difference between the two components, but the subtle chemical tweak — akin to writing a letter in a hard-to-read, byzantine font — gives an entirely different meaning for the ribosome, the researchers suggest.

The result is “groundbreaking,” says Nina Papavasiliou, a molecular biologist at Rockefeller University in New York City. “It says that we don’t fully understand how ribosomes decode RNAs.”

That discovery could also mean that genes contain more information than scientists have realized, Papavasiliou says.

Pseudouridine is already known to be important for the function of many types of RNA in cells. Yu and Karijolich engineered a system to discover whether mRNAs containing the modified letter might also have a slightly different function than those with plain old uridine. The researchers created a flawed copper-detoxifying gene called CUP1 that contained an early signal to stop making protein. The team also created a system that would cause yeast cells to edit the mRNA, replacing the uridine in the stop codon with pseudouridine. If pseudouridine behaved just like uridine, then cells would prematurely halt production of the detoxifying protein and wouldn’t be able to grow in the presence of copper.

Yeast cells that replaced uridine in the stop sign with pseudouridine could grow on copper, the researchers found. Looking more closely, the team found that instead of reading the stop sign as stop, ribosomes interpreted the pseudouridine-containing codon as an instruction to insert the amino acids serine, threonine, phenylalanine or tyrosine into the protein.

That choice of amino acids by the ribosome has biologists reeling, because those aren’t even the amino acids usually chosen when the protein factories do occasionally run stop signs.

“When you know the literature, you would expect other [amino acids],” says Henri Grosjean, a biochemist and geneticist at the University of Paris-South.

Apparently ribosomes haven’t read those papers.

Whether pseudouridine plays a part in changing the genetic code in nature remains to be seen, but researchers are betting that it does. The implications for health and disease could be great, says Juan Alfonzo, a molecular biologist at the Ohio State University. Pseudouridines may be required to make some proteins correctly, but “misplacing a pseudouridine could make things a physiological mess,” he says, causing some proteins to have flaws, even fatal ones.

And Yu and Karijolich’s technique might be used to fix genetic errors, too. Introducing stop sign–busting pseudouridine into an RNA may one day help people with rare genetic diseases in which one of their genes contains an early stop codon, Alfonzo says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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