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May 17, 2007

Two Studies Provide New Insights on miRNA’s Silencing Mechanism

  • A couple of new studies, published online in the May 16 issue of Nature, discovered novel mechanisms for the gene silencing abilities of miRNA.

    Researchers from the European Molecular Biology Laboratory (EMBL) examined miRNAs in a test tube, which revealed that they block the initiation of translation.

    Applying a new system for studying miRNA’s interaction with mRNA in a test tube, the researchers discovered that miR2, an important miRNA in fruitflies, blocks translation early on, even before the cellular machinery needed can assemble. Bound by miR2, a mRNA molecule is no longer accessible to ribosomes.

    "Strikingly, the messenger RNA locked-up in this way looks similar to a messenger RNA that undergoes translation," says Rolf Thermann, Ph.D., postdoctoral fellow at EMBL. "It is bound by big microRNA complexes that strongly resemble ribosomes, but they are not. This explains why when looking at already locked-up messenger RNA many scientists thought that translation had already started and microRNAs must interfere at a later stage of the process. It will be exciting to determine what these complexes are made of and how exactly they function."

    In the second, unrelated study, a team of scientists at The Wistar Institute and the University of California, San Diego, found one of the molecules involved in the miRNA complex that inhibits translation.

    “By tracking the associations between molecules involved in generating microRNAs and other molecules in the cell, we uncovered an entirely new pathway, one that led us to a mechanism that blocks the cellular machinery that produces a protein from messenger RNA," explains Ramin Shiekhattar, Ph.D., professor in the Gene Expression and Regulation Program and the Molecular and Cellular Oncogenesis Program at Wistar and senior author on the study.

    In earlier studies, Dr. Shiekhattar identified a three-molecule complex known as RISC and showed that it plays a vital role in generating miRNAs. In the current study, the researchers extended those finding to discover that RISC also interacts with another complex that includes molecules required to build functional ribosomes. Closer investigation showed that the new complex also included a component called eIF6. This molecule is known to interfere with the proper assembly of ribosomes, which prevents them from doing the work of translating mRNA into a protein.

    "We wondered if certain microRNA-responsive genes might be attracting microRNAs that then recruited eIF6 to that location," Dr. Shiekhattar says. "If so, the eIF6 would prevent the assembly of a competent ribosome, thus blocking messenger RNA translation at that gene. The result would be to silence that specific gene. We tested this idea in human cells and in worms and found it to be the case in both."



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