Researchers across the world have been trying to answer the question of how RNAi works for many years. A research group headed by Prof. Renée Schroeder (MFPL) and Dr. Javier Martinez (IMBA) based at the Campus Vienna Biocenter says they have come closer to finding an answer.
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. The first treatments to be based on this mechanism are currently undergoing clinical testing.
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 outa check to ensure that it is only certain RNAs that are destroyed," explains Dr. Ameres.
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.
"Molecular Basis for Target RNA Recognition andCleavage by human RISC", S.L. Ameres. J. Martinez, R. Schroeder. CELL (2007). doi:10.1016/j.cell.2007.04.037