Biochemical interaction of viral and cellular miRNAs

Coordinator:    Prof. Dr. Klaus Förstemann
Institution: Genzentrum, LMU München
The discovery of post-transcriptional regulation by miRNAs has refined and extended our understanding of cellular control mechanisms. These small RNAs serve as guides to recognize specific mRNAs via partial complementarity of the respective nucleotide sequences. With the help of their associated protein factors, miRNAs prevent the translation of these mRNAs. Viruses have also developed their own miRNAs as tools to re-program the host cell. In the context of the NGFN-plus consortium “Pathogenetic Role of miRNAs in Herpesvirus Infection” our subproject examines a biochemical step during the generation of miRNAs and its possible importance for proliferation of the virus.
Biogenesis of miRNAs occurs through a cascade of nucleolytic processing reactions, during which a larger precursor molecule is successively trimmed until the mature, single-stranded miRNA is finished. In parallel to these “manufacturing” steps, the miRNA must transition between different protein complexes in a defined order to ensure that the intended fragment is excised from the longer precursor. At the final step of biogenesis, however, miRNAs in human cells have the possibility to become incorporated into four different protein complexes with distinct properties. This enlarges the spectrum of possible effects a miRNA can exert: While the base sequence of the miRNA determines which mRNAs are targeted, the proteins associated with it determine what exactly will happen with these mRNAs.
It seems sensible, therefore, that miRNAs are not randomly distributed into the four so-called effector-complexes, but rather sorted to an individually predetermined extent into each of these complexes. This could be demonstrated e.g. for cellular miRNAs in the fruitfly Drosophila melanogaster. We now want to extend these observations to the biology of herpesvirues. Specifically, we will examine if such a sorting step exists in human cells and whether it is a site of forceful interaction with the cellular miRNA system that is important during the virus/host arms race. 
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