RNA Interference - Decision-Making Processes on a Molecular Level

"How does RNAi work?" Researchers across the world have been trying to answer this question for a number of years. Science has now come closer to finding the answer thanks to a research group headed by Prof. Renée Schroeder (MFPL) and Dr. Javier Martinez (IMBA) based at the Campus Vienna Biocenter. The group's results are being published today in the internationally renowned scientific journal CELL and underline the importance of Austrian RNA research, which is also supported by the Austrian Science Fund FWF.

Schematic representation of a RISC/target RNA interaction. The recognition of target RNA (blue) by RISC (red) can be likened to the principle of a zip fastening. Closing the zip eventually leads to the elimination of unwanted or harmful RNA in the cell. © Use of this photo for editorial purposes is free of charge, subject to attribution: IMP graphics department

RNA interference (RNAi) is a natural cellular defence and regulation mechanism which works by eliminating unwanted RNA molecules. Its potential for use in therapy was officially recognised last year with the presentation of the Nobel Prize in Physiology or Medicine. Indeed, the first treatments to be based on this mechanism are currently undergoing clinical testing. Nevertheless, the details of this process still require a great deal of further research and hence, offer potential for optimizing medical treatments based on it.

No RISC. No Fun.
It is precisely this potential that a group at the Campus Vienna Biocenter recently tapped in order to clarify key details surrounding the efficiency of RNA interference. Lead scientist Dr. Stefan L. Ameres from the Max F. Perutz Laboratories (MFPL), Department for Biochemistry at the University of Vienna, explains - "A key stage of RNA interference is the binding of the RNA that is to be cleaved by RISC, the RNA-induced silencing complex. Already a lot is known about the subsequent destruction of the target RNA by RISC, but we have only little insight into the initial determination as to which RNAs are bound and how exactly this happens. Working with the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), we have succeeded in making considerable progress towards clarifying this process."

The team initially focussed on characterising the influence of the RNA structure. Variations of an RNA target molecule were created where the RISC binding site became increasingly difficult to access due to structural differences. Dr. Ameres comments on the findings from the experiment: "The results were very clear indeed. The less accessible the binding site, the less efficient the RISC-induced elimination of the target RNA. Based on this data, we concluded that RISC does not possess the means to change the structure of RNA molecules - an important finding towards the effective application of RNAi."

Another result was equally important to the understanding of RNA interference. The strength of the interaction between target RNA and RISC must exceed a certain threshold in order to trigger initiation of the subsequent RNA elimination process. This result clearly indicates that RISC binds RNA in a more or less random process and that it is the strength of this bond that determines the subsequent fate of the RNA. "One way of looking at this is that, while binding its target RNA, RISC has to carry out a check to ensure that it is only certain RNAs that are destroyed," explains Dr. Ameres.

"Ph.D. Program" Career Opportunity
The publication of these results in the journal CELL highlights not just the quality of RNA research at the Max F. Perutz Laboratories (a joint establishment of the University of Vienna and the Medical University of Vienna), but also the high standard of training provided for young scientists in dedicated Ph.D. programs. The publication of these results is also the high point of Dr. Ameres' Ph.D. training, which he has now completed in just this type of program. In fact, a special "RNA Biology" Ph.D. program was established at the Campus Vienna Biocenter in June 2007 to ensure that RNA research there retains its leading position in the long term. The work of molecular biologist Prof. Renée Schroeder also contributed to this achievement. She supported the work of Dr. Ameres using the prize money from the "Wittgenstein Award" presented to her by the FWF in 2003, thereby making an important financial contribution to the continuation of RNA research at the Campus Vienna Biocenter.

Original publication: Molecular Basis for Target RNA Recognition and Cleavage by human RISC. S.L. Ameres. J. Martinez, R. Schroeder. CELL (2007). doi:10.1016/j.cell.2007.04.037

Scientific contact
Dr. Stefan L. Ameres
Max F. Perutz Laboratories
Universität Wien
Campus Vienna Biocenter 5
1030 Vienna, Austria
T +43 / 1 / 4277 - 54693
stefan.ameres(at)univie.ac.at

Austrian Science Fund FWF
Mag. Stefan Bernhardt

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