Mechanisms of microRNA gene silencing revealed
silences genes and prevents protein production, which could lead to
new anticancer therapies.
In the first study, researchers at European Molecular Biology Laboratory (EMBL) developed a new way of investigating how microRNA (miRNA) binds to messenger RNA (mRNA) and prevents it from translating a gene's DNA into proteins - the molecules that carries out a given gene's function. Over 30 per cent of all human genes are regulated by around 500 microRNAs. They regulate many crucial processes like cell division and development and play an important role in various diseases including cancer, diabetes and viral infections. "So far it has been impossible to directly examine how and when microRNAs lock up messenger RNAs," said Matthias Hentze, associate director of EMBL, "because until now all we could look at were messenger RNAs that had already been locked-up within cells." "To investigate the locking process itself, we developed a test tube system that recreates close to real life conditions of fruit fly embryos. Adding messenger RNAs to this system we could monitor for the first time how they got locked-up by microRNAs." The scientists discovered that a microRNA called miR2 binds to messenger RNA molecule and makes it no longer accessible to ribosomes, the complexes that carry out protein synthesis. "Strikingly, the messenger RNA locked-up in this way looks very similar to a messenger RNA that undergoes translation," said Rolf Thermann, who carried out the research. "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." A second study from scientists at The Wistar Institute and the University of California, both US, has discovered an alternative method that microRNAs use to prevent protein production. "Some microRNAs closely match their sequences against particular messenger RNA sequences to target them for destruction," explained Professor Ramin Shiekhattar, at Wistar. "That's one way we know that microRNAs can silence genes. That mechanism requires extraordinary specificity, however, and we suspected that microRNAs were also acting in some other way to inhibit gene translation into protein." Prof Shiekhattar had previously identified a three-molecule complex known as RISC and showed that it plays a vital role in generating microRNAs. Armed with that knowledge, he has now tracked the associations between RISC and other molecules in the cell. They found 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 messenger RNA into protein. "We wondered if certain microRNA-responsive genes might be attracting microRNAs that then recruited eIF6 to that location," said Shiekhattar. "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." The team then tested this idea in human cells and in worms and found it to be the case in both. "Interestingly, this not only supported our hypothesis, but to see it in such different organisms also suggested that the mechanism involved has long been conserved in evolution," explained Shiekhattar. Both studies are published in the 16 May edition of Nature.
