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Diploma thesis
PhD thesis

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  Group: Silke Dorner

Elisabeth Jäger | PhD Student
Denise Herold | Diploma Student

Post-transcriptional gene regulation by miRNAs and siRNAs

Post-transcriptional processes such as mRNA splicing, mRNA degradation, mRNA surveillance, RNA editing, translational repression and RNA-mediated gene silencing play crucial roles in the regulation of eukaryotic gene expression. In the past decade the finding of small non-coding RNAs has entirely revolutionized the way we think about the regulation of gene expression. The major focus of our research is the RNA-mediated gene silencing by siRNAs (small interfering RNAs) and miRNAs (micro RNAs) in Drosophila.
siRNA mediated gene silencing or RNA interference (RNAi): RNA interference is thought to be a mechanism used to defend viruses and other transposable element. RNAi is initiated by double-stranded RNAs (dsRNAs) that are processed into short interfering RNAs (siRNAs). siRNAs get incorporated into the RNA-induced silencing complex (RISC) which ultimately targets homologous mRNAs for degradation. We performed a genome-wide screen for components of the siRNA pathway and identified several novel candidate genes in Drosophila cultured cells. The main focus of this project is the biochemical characterization of these novel candidate genes. This will allow the identification of their role in the siRNA pathway.
miRNA-mediated gene silencing: MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs (about 22 nt) that are found in a variety of eukaryotic organisms. Over the past decade these small RNAs emerged as crucial factors of gene regulation and play an essential role in developmental and physiological processes. Generally, animal miRNAs base pair imperfectly to the 3’ untranslated region (3’ UTR) of target mRNAs and have been well established as key regulators of gene expression at the translational level. More recently evidence accumulated that miRNAs can also accelerate mRNA degradation of some of their targets. It is important to note that miRNA-mediated decay of mRNA does not occur through an endonucleolytic cleavage as in siRNA-mediated gene silencing. However, miRNAs accelerate the mRNA turnover by recruitment of the general mRNA decay machinery. The underlying mechanisms by which miRNAs regulate gene expression are still quite controversial. The aim of this project is to develop kinetic tools to study the mechanism by which miRNAs affect the stability and translatability of their target mRNA. Thus, we will investigate which particular step of mRNA degradation or translation is influenced by miRNAs.

Selected recent publications

Eulalio A., Rehwinkel J., Stricker M., Huntzinger E., Yang S-F., Doerks T., Dorner S., Bork P., Boutros M. and Izaurralde E. (2007) Requirement for enhancers of decapping in miRNA-mediated gene silencing, Genes and Development 21, 2558-70.

Dorner S., Eulalio A., Huntzinger E. and Izaurralde E. (2007). Meeting Report: Delving into the diversity of silencing pathways, Symposium on MicroRNAs and siRNAs: Biological Functions and Mechanisms, Embo Reports 8,723-9.

Dorner S, Lum L, Kim M, Paro R, Beachy PA, Green R. (2006). A genomewide screen for components of the RNAi pathway in Drosophila cultured cells, Proc Natl Acad Sci U S A. 103, 11880-5.

Dorner S., Brunelle J.L., Sharma D., Green, R.(2006). The hybrid state of tRNA binding is an authentic translation elongation intermediate, Nat. Struc. Mol. Biol. 13, 234-41.