Scientists may have uncovered a new level in the hierarchy of biological information embodied in RNA. Specifically, they have found that the RNA genome of an HIV-1 virus contains many highly structured regions (Nature 2009, 460, 711).
Researchers at the University of North Carolina (UNC), Chapel Hill, and the National Cancer Institute, in Frederick, Md., propose that the level of complexity of the RNA genome's architecture correlates with the structure of the proteins it encodes and with the location of splice (enzymatic cleavage) sites in the RNA.
Postdoc Joseph M. Watts, chemistry professor Kevin M. Weeks, and coworkers revealed HIV's RNA architecture with a previously developed chemical method called SHAPE (selective 2´-hydroxyl acylation analyzed by primer extension), which gauges the conformational flexibility of individual nucleotides in an RNA sequence (J. Am. Chem. Soc. 2005, 127, 4223). The higher the SHAPE reactivity, the more flexible a particular nucleotide is. The researchers converted the measured SHAPE reactivities into free energies, which they used to predict the secondary structure of RNA.
The study shows that "the HIV genome is packed full of structures," Weeks says. "Right away, we knew that we needed to prove that these structures were not an accident." In collaboration with virologists Ronald Swanstrom and Christina L. Burch at UNC, the researchers find that these structures occur in many HIV variants and are therefore likely to play critical roles in viral replication.
They don't yet know the function of all these structured regions, but they hypothesize that many help determine the structure of the proteins encoded by those sequences. Weeks suspects that regions that are more highly structured move slowly through the ribosome as it translates the RNA into proteins. "The idea is that the ribosome pauses close to the end of every protein domain to allow that domain to fold up into its correct shape, without interference from the other domains of the protein," he says.
The researchers also find that highly structured regions in the RNA encode relatively simple loop regions in proteins. "We've essentially looked at a single data point. As more RNAs are evaluated, this might become a general rule," Weeks says. "If that's true, then it might be appropriate to think of RNA structure as another level of the genetic code."
"The possibility that the genome's three-dimensional shape is being used for a hierarchy of control on the production of proteins and the fate of the genome itself is fascinating," says Michael Yarus, a biology professor at the University of Colorado, Boulder. "Anybody who is interested in a unified picture of an organism's genetic activity will be interested in a detailed reading of the novel genomic features that appear in the complete secondary structure" of HIV's RNA.