Researchers Identify Enzyme That Turns On RNA

MADISON - Knowing an organism's genome is good, but knowing what turns on its genes is even better.

Scientists have long searched for triggers that activate ribonucleic acid (RNA), a key component in gene expression. Now, in the Thursday, Sept. 19 issue of the journal Nature, scientists from the University of Wisconsin-Madison report that they have found an enzyme that activates RNA, which could lead to new ways of regulating genetic information.

"One of the big questions in molecular biology is how genes are controlled," says Judith Kimble, a Howard Hughes Medical Institute investigator, a UW-Madison professor of biochemistry and senior author of the paper. "Our finding provides an important piece of the puzzle."

Inside the nucleus of every cell are genes, which are composed of deoxyribonucleic acid (DNA). This genetic information contains all the instructions cells need to make proteins, molecules that enable cells to carry out special functions, such as the transport of oxygen by red blood cells. For these cellular activities to happen, DNA must get copied into RNA, which carry the instructions outside the nucleus to the molecular machinery that makes proteins.

But along the way, things can go awry: If an RNA isn't activated, Kimble says, "it can get trashed or hidden away. And, if the cell doesn't have a particular RNA, it won't have any of the protein the RNA encodes."

Liaoteng Wang, lead author of the article and a graduate student in Kimble's lab, adds, "a gene won't do any good if it fails to be expressed."

By studying the embryonic development of the microscopic worm, C. elegans, Kimble and Wang, as well as Marvin Wickens and Christian Eckmann also from UW-Madison's biochemistry department, identified two proteins - GLD-2 and GLD-3 - that, when bound together to form an enzyme, activate specific RNAs outside the nucleus. This activation would enable the RNA to carry out important steps of germ line, or reproductive, development, such as the formation of sperm or egg cells. In other words, RNA wouldn't get "trashed."

"People had been looking for this enzyme for a long time," says Kimble. "We were incredibly lucky. We found it serendipitously."

As Kimble explains, Wang and Eckmann had been working independently on the different proteins, both of which are responsible for most stages of germ line development. Wang studied GLD-2 and found that it had a site where reactions could take place, but that it couldn't bind to an RNA. Eckmann, who studied GLD-3, found that his protein could do just the opposite: it could bind to an RNA, but didn't have the catalytic site.

"Wang and Eckmann started looking for binding partners for their individual proteins and, amazingly, they found that GLD-2 and GLD-3 bound to each other," says Kimble.

Binding the two proteins together created an enzyme that could not only attach itself to RNA but could also chemically modify the RNA in a specific way that turns it on. And, as Kimble says, "When regulating biologic processes, you don't want to activate all the RNAs in a cell - you want to activate only the important RNAs at the right time and in the right place."

Researchers have found homologs, or proteins similar to GLD-2, in other organisms, ranging from yeast to humans. Little is known about these homologs, except their amino acid sequences, says Kimble. Proteins similar to GLD-3 have also been found, but only in more complex animals, ranging from worms to humans. Again, how these proteins work remains a mystery.

"More and more organisms' genomes have been completely sequenced, but sequences don't tell you the biochemical function of proteins," says Wang. "In this study, we identified the biochemical function of GLD-2, and, since there are proteins in other organisms that have sequences similar to this protein, we can now make more educated guesses about the function of those proteins. It is the idea of 'one stone, many birds.'"

By identifying this enzyme that regulates how genes are expressed in C. elegans, the researchers say it will now be possible for scientists to explore how similar enzymes work in humans, possibly one day leading to new therapies. Says Kimble, "I think this is a big finding for anyone interested in how genes are regulated."