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At first, we thought that gene expression was modulated only by transcription factors. Then we found that the RNA resulting from transcription could be regulated by the RISC complex (siRNA-mediated degradation via Dicer). And now it seems that regulation at the RNA level is even more complex than we first imaginated...

As any dedicated video game player knows, the first requirement for using a weapon or tool is finding it. And it is no different for cell biologists and clinicians who want to take control of gene expression in cells to create therapies to treat disease. While cells have a variety of ways to control gene expression, the trick for players in this game is to recognize them amidst the incredibly complex background of cellular machinery.

Now, in a paper in the January 28th issue of Cell, Lynne E. Maquat, Ph.D., professor of Biochemistry and Biophysics at the University of Rochester Medical Center, and her team have identified a novel pathway for RNA degradation, a form of regulation that has garnered significant attention in recent years, and one that has the potential to produce a new set of tools for physicians to use to fight disease.

Most of the gene-control tools researchers have collected thus far involve the first step in gene expression, in which DNA is copied into RNA transcripts. However, recent discoveries have shown that many of the tools cells use to regulate genes work after transcription, by moderating the activity and the life span of the RNA itself.

One major pathway for such post-transcriptional regulation is called nonsense-mediated decay (NMD). Originally NMD was thought to destroy incorrectly transcribed or otherwise problematic RNAs, but investigators now know that it plays a major role in regulating the life span of numerous RNAs, and thus controls gene activity.

To better understand what controls the NMD system, Maquat and her postdoctoral fellow, Yoon Ki Kim, Ph.D., used a critical c omponent of the NMD complex, Upf1, as bait in a molecular fishing expedition. With this approach, proteins that naturally interact with the bait will be pulled out of the pool of cellular proteins.

They found that Upf1 grabbed onto Staufen1 (Stau1). Stau1 is a well-known RNA binding protein and some of its functions in the common fruit fly Drosophila are understood. "But no one knew what Staufen1 did in human cells," said Maquat, even though its presence in mammalian cells has been recognized for several years.

"We were surprised to find that Staufen1 interacts with Upf1," she added. "This is a whole new function for Staufen1 that couldn't have been predicted from the studies in flies, even though a similar function may occur in flies."

The team discovered that Staufen1 doesn't interact with other components of the NMD complex ?and altering the amount of Staufen1 in the cell didn't change NMD function. Those observations, said Maquat, sent Kim on a hunt for what Staufen1 and Upf1 were doing.

Looking at gene expression data available through the lab of Luc DesGroseillers, Ph.D. at the University of Montreal, they found that Staufen1 protein binds to numerous RNAs. Downregulating the amount of Staufen or Upf1 increased the half-life of these RNAs. Significantly, altering the amount of another NMD factor didn't affect these RNAs.

Thus, Staufen1 and Upf1, together, degrade RNAs by a previously undescribed mechanism, which the team called Staufen1-mediated degradation (SMD). Preliminary results suggest that SMD activity affects numerous transcripts and, therefore, is a novel mechanism of gene regulation.

"We don't yet understand how SMD is regulated but it must be," said Maquat. "Both Upf1 and Staufen1 can be phosphorylated, so their activities could be regulated by cell signaling pathways, such as those mediated by changes in growth conditions." That would allow the cell to differentially control the level of SMD-target RN As, while leaving the NMD-regulated RNAs untouched.

This is likely to be the "tip of the iceberg" for Staufen1's function in mammalian cells, said Maquat, and just the beginning of the SMD story as well.



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