RNAs taking centre stage
Saturday, 12 September 2009
In an article published in Nature, scientists at the Friedrich Miescher Institute for Biomedical Research (part of the Novartis Research Foundation) have shown that short strands of ribonucleic acid (RNA) which regulate protein production are themselves also regulated. This additional layer of regulation opens up new perspectives for therapeutic approaches.
RNAs, serving as a mere intermediary between DNA and proteins, were long regarded as a poor relation by researchers, attracting little interest. However, following the discovery of small RNAs known as microRNAs, they have increasingly been moving into the limelight. MicroRNAs bind to messenger RNA (mRNA), thereby regulating the translation of genes into proteins.
Recently, various studies have shown that the production of microRNAs is tightly controlled, but their subsequent fate was not clear. It was assumed that mature microRNAs remained stable in the cell for days, and that their possible functions were therefore restricted: a microRNA persisting for a relatively long period cannot be involved in any processes in the cell requiring rapid adaptation.
The study carried out by Helge Grosshans, a Research Group Leader at the Friedrich Miescher Institute, has now finally shifted attention away from DNA, spotlighting the key role played by microRNAs in the theatre of cellular processes. As Grosshans and his team report in the current issue of the renowned journal Nature, they discovered a mechanism for active degradation of microRNAs and showed that this mechanism is itself regulated.
Explaining his findings, Grosshans says:
"What was formerly conceived of as a direct, straightforward pathway is gradually turning out to be a dense network of regulatory mechanisms: genes are not simply translated into proteins via mRNA. MicroRNAs control the translation of mRNAs into proteins, and proteins in turn regulate the microRNAs at various levels."
In addition, the FMI researchers showed in the nematode Caenorhabditis elegans that, via regulation of degradation, it is possible to influence microRNA activity. This means that microRNAs may, after all, be involved in the regulation of rapidly occurring processes.
The meteoric rise of microRNAs
MicroRNAs are short, single-stranded RNA molecules which interact with mRNAs in a sequence-dependent manner. They thus inhibit translation of mRNAs into proteins. MicroRNAs were first described in 1993 in the nematode Caenorhabditis elegans. They were subsequently also shown to play an important role in regulating development processes and in pathogenesis in higher organisms. The findings of recent years and now also Helge Grosshans's study have shifted attention away from DNA toward RNAs, which are taking centre stage. The term "microRNA" was only introduced in 2001.
Targeted degradation of disease-causing RNAs
But the findings are also relevant in another respect. As microRNAs have been implicated in the development of diseases, efforts to date have focused on replacing disease-causing microRNAs with other microRNAs, or inactivating them with the aid of complementary RNA strands. Unfortunately, it is extremely difficult to deliver RNAs to target cells for therapeutic purposes. Accordingly, the prospects of success for these novel treatment approaches have been uncertain.
In his study, however, Grosshans identified a protein that specifically degrades microRNAs. If it now proves possible to specifically activate or inhibit this protein and its partners that could provide an approach, which is closer to classical and well-established forms of therapy.
"We now assume that a large number of human genes are regulated by microRNAs, so the regulatory mechanism we've discovered has a great potential to significantly influence numerous processes in human cells," Grosshans comments.
About the FMI
The Friedrich Miescher Institute for Biomedical Research (FMI), based in Basel, Switzerland, is a world-class centre for basic research in life sciences. It was founded in 1970 as a joint effort of two Basel-based pharmaceutical companies and is now part of the Novartis Research Foundation. The FMI is devoted to the pursuit of fundamental biomedical research. Areas of expertise are neurobiology, growth control, which includes signalling pathways, and the epigenetics of stem cell development and cell differentiation. The institute counts 320 collaborators. The FMI also offers training in biomedical research to PhD students and postdoctoral fellows from around the world. In addition, the FMI is affiliated with the University of Basel. The Director of the FMI since 2004 is Prof. Susan Gasser.
Active turnover modulates mature microRNA activity in C. elegans
Chatterjee S & H. Grosshans
Nature, 24 August 2009, doi:10.1038/nature08349
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