Scientists from the University of California, San Diego School of Medicine and Indiana University say they have identified a protein that regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the many proteins necessary for life.
According to the researchers, the study (“The dsRBP and Inactive Editor ADR-1 Utilizes dsRNA Binding to Regulate A-to-I RNA Editing across the C. elegans Transcriptome”), published in Cell Reports, helps explain how a relatively limited number of genes can provide versatile instructions for making thousands of different messenger RNAs and proteins used by cells in species ranging from sea anemones to humans. In clinical terms, the research might also help researchers parse the underlying genetic mechanisms of diverse diseases, perhaps revealing new therapeutic targets, they add.
“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer, and blood disorders,” said Gene Yeo, Ph.D., assistant professor in the department of cellular and molecular medicine at UC San Diego. “This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides a method to screen for them and opens up new ways to study human biology and disease.”
“To be properly expressed, all genes must be carefully converted from DNA to messenger RNA, which can then be translated into working proteins,” added Heather Hundley, Ph.D., assistant professor of biochemistry and molecular biology at Indiana University and co-senior author of the study.
RNA editing alters nucleotides within the mRNA to allow a single gene to create multiple mRNAs that are subject to different modes of regulation. How exactly this process can be modulated, however, has never been clear.
Using the nematode C. elegans as their model organism and a novel computational framework, Drs. Hundley, Yeo, and colleagues identified more than 400 new mRNA editing sites, the majority regulated by a single protein called ADR-1, which does not directly edit mRNA but rather regulated how editing occurred by binding to the messenger RNAs subject to editing.
“Despite lacking deaminase function, ADR-1 affects editing of over 60 adenosines within the 3 UTRs of 16 different mRNAs. Furthermore, ADR-1 interacts directly with ADR-2 substrates, even in the absence of ADR-2, and mutations within its double-stranded RNA (dsRNA) binding domains abolish both binding and editing regulation,” wrote the investigators. “We conclude that ADR-1 acts as a major regulator of editing by binding ADR-2 substrates in vivo. These results raise the possibility that other dsRNA binding proteins, including the inactive human ADARs, regulate RNA editing through deaminase-independent mechanisms.”
The scientists noted that a protein similar to ADR-1 is expressed by humans, and that many of the same mRNA targets exist in people, too. “So it is likely that a similar mechanism exists to regulate editing in humans,” said Dr. Hundley, adding that she and colleagues will now turn to teasing out the specifics of how proteins like ADR-1 regulate editing and how they might be exploited “to modulate editing for the treatment of human diseases.”