A novel way of editing genetic messages.

A novel way of editing genetic messages

Imagine deciphering a coded message but having no way to trace its origin. Molecular geneticists have faced this frustration ever since the 1986 discovery that cells of many organisms, from protozoans to people, contain extra bits of genetic information that aren't obviously encoded by the DNA in their genes.

The extra information appears in messenger RNA (mRNA). DNA routinely transcribes mRNA molecules to shuttle its message to the cell's protein-synthesis machinery, which translates the message into proteins. But the discovery that extra genetic material subsequently gets added into certain mRNA molecules--a process called RNA editing -- has left scientists searching for the DNA-like molecular template that encodes the edited mRNA sequences.

Now, researchers think they have identified the source of the added material. Working with mitochondrial DNA from the protozoan Leishmania tarentolae, the team has found evidence that some DNA molecules nestled between genes -- and previously considered inactive -- serve as templates for a newly recognized class of small RNA molecules that carry out the editing process. The researchers call these RNA molecules "guide RNA" (gRNA).

"RNA editing is a novel mechanism of information transfer between RNA molecules," says Larry Simpson of the university of California, Los Angeles, who coauthored the report in the Jan. 26 CELL. In the mechanism his group proposes, short gRNA molecules form a double-stranded complex with certain mRNA molecules. The gRNA edits the mRNA by specifying the addition or deletion of an RNA building block called uridine. Adenine, uridine, guanine and cytosine are the four building blocks, or bases, that make up RNA.

When DNA transcribes mRNA, the sequence of bases in the DNA leads to a complementary sequence in the mRNA. Scientists have traditionally recognized adenine-uridine and guanine-cytosine as the complementary base pairs in RNA. But in their new model, Simpson's group considered the possibility of a third complementary base pair: guanine-uridine. Though unusual, this pairing has been observed in other types of RNA molecules. Simpson asserts that the failure to recognize guanine-uridine pairing has hindered scientists in their search for missing template.

In RNA editing, wherever a guanine or an adenine occurs on the gRNA side of the mRNA-gRNA complex, a uridine is added to the mRNA sequence, he says. Because this mRNA must be edited before it can get translated into proteins, the editing step essentially regulates protein synthesis, Simpson suggests.

The researchers do not yet know whether their proposed mechanism applies to RNA editing in other organisms and cell types. "It is possible that the RNA-based mechanism could work for other types of RNA editing in plants and humans, but there is no evidence of that," Simpson cautions.

Even so, their report has raised the spirits of scientists puzzled by the editing phenomenon. "It's fabulous," says biochemist Alan M. Weiner at Yale University. "The finding is the beginning of a revolution of something that has driven us all crazy."

Gerald F. Joyce of the Research Institute of Scripps Clinic in La Jolla, Calif., adds, "They clearly have the answer to the big question, which is: Where is the template?"

But another new study hints that the search may not have ended. In the Feb. 1 NATURE, Vladimir Volloch and his colleagues at the Boston Biomedical Research Institute describe their work with the protozoan Trypanosoma brucei, which causes African sleeping sickness. Their findings seem to contradict Simpson's. They indicate that the bulk of edited RNA is synthesized during rather than after mRNA transcription from a still-unidentified template that produces only edited mRNA. The researchers add, however, that their method may not have been sensitive enough to detect editing taking place after mRNA transcription.

Simpson says his team hopes to generate edited mRNA in vitro by adding gRNA of a known sequence to synthetic, pre-edited mRNA. This, he told SCIENCE NEWS, would prove that RNA editing takes place in preexisting mRNA molecules.