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Possible target found for boosting microRNA action

May 16, 2007 By Heidi Ledford This article courtesy of Nature News.

Study shows how micro molecules interfere with gene expression.

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Tiny fragments of RNA called microRNAs are known to interfere with gene expression, but how? A new study hints that they get involved right at the start of the game — they seem to prevent protein production before it even starts.

The finding, published online this week in Nature, provides a key to understanding how microRNAs dial down the expression of genes, and hints at a new drug target1. That could lead to new avenues for cancer therapies, says Ramin Shiekhattar, a biochemist at the Centre for Genomic Regulation in Barcelona, Spain, and an author of the study.

Since their discovery in 1993, microRNAs have cropped up nearly everywhere. They regulate stress, disease and development. They operate in plants, insects and mammals. Roughly 600 human microRNAs have been isolated so far, and expression of as much as a third of the human genome could depend on the diminutive molecules.

But even as the microRNA tally rises, researchers have struggled to determine how they restrict gene expression. It was clear that they interfere with the translation of RNA into protein, but at which step in the process?

"There is a lot of controversy regarding the mechanism," says Wiltold Filipowicz, a biochemist at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. "People are boxing over this at meetings."

Shiekhattar, then at the Wistar Institute in Philadelphia, Pennsylvania, and his colleagues addressed the question by isolating complexes of proteins known to be involved in microRNA function. They found that the complexes interacted with a protein called eIF6, which inhibits assembly of the molecular machinery needed to read the RNA code and churn out the corresponding protein.

To find out whether eIF6 was necessary for microRNA to function, the team cut down levels of the protein and looked to see whether three microRNAs — two in human cells and one in a nematode worm — could still reduce expression of their target genes. In all cases, cells with less eIF6 had less microRNA function.

Machine making

Because eIF6 is necessary for the translation machinery to form, their finding implies that microRNAs prevents protein production from starting.

That's in line with some published literature, but conflicts with other experiments showing that microRNAs act at a later stage of protein production.

"There are a whole series of papers that all present very sound experimental evidence, but suggest that different steps of translation are the target of this mechanism," says Thomas Preiss, a molecular geneticist at the Victor Chang Cardiac Research Institute in Darlinghurst, Australia. Preiss says that the easiest way to reconcile the conflicting data is to assume that several mechanisms are at play.

Brandon Ason, a molecular biologist at the University of California, San Francisco, agrees. "This is definitely strong evidence that eIF6 is at play," he says, "but it doesn't rule out other models."

Another possible reason for the confusion is highlighted in a second Nature paper this week2. Work in fruit flies shows that some RNAs targeted by microRNAs are associated with broken translation machinery. This could have misled some researchers, who assumed that protein production had started as normal, and that microRNAs interfered with it further down the chain — when in fact protein production couldn't have started in the first place.

MicroRNAs are thought to be involved with cancer: their levels are reduced in cancerous cells3, and repressing microRNA processing can encourage tumour formation4. So finding a protein involved with microRNA function leads to a new drug target to help boost their function and hopefully protect against cancer. "If you manipulate eIF6, you're going to globally effect microRNA levels," says Shiekhattar.

References

  1. Chendrimada T. P., et al. Nature, doi:10.1038/nature05841 (2007).
  2. Thermann R. & Hentze M. W. Nature, doi:10.1038/nature05878 (2007).
  3. Lu J., et al. Nature, 435 . 834 - 838 (2007).
  4. Kumar M. S., Lu J., Mercer K. L., Golub T. R. & Jacks T. Nature Genet., 39 . 673 - 677 (2007).

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