| Speaker | Jörg Hackermüller |
| Title | The RNA secondary structure dependence of RNA protein
interactions and its implications for the post transcriptional regulation of gene expression |
Controlled and specific recognition of RNA by ligands (especially proteins) is of great importance for many cellular processes, particularly in of gene expression. RNA-ligand binding often depends crucially on the local RNA secondary structure at the binding site. We develop here a model that quantitatively predicts the effect of RNA secondary structure on effective RNA-ligand binding activities based on equilibrium thermodynamics and the explicit computations of partition functions for the RNA structures. A statistical test for the impact of a particular structural feature on the binding affinities follows directly from this approach. The formalism is extended to describing the effects of hybridizing small ``modifier RNAs'' to a target RNA molecule outside its ligand binding site.
We apply the developed methods to suggest a solution for an important unsolved question in AU-rich element (ARE) dependent regulation of mRNA stability. This pathway seems to be responsible for the accurate regulation of several thousand genes. While several negative regulators have been identified for this system, there is only a single, ubiquitously expressed protein known that upon binding stabilizes mRNAs in a highly stimulus and target specific manner, . How the high level of specificity observed in mRNA stabilization by is ensured is fundamentally unclear.
We derive an RNA sequence/structure motif for binding from experimental affinity data and show how modifier RNAs can be used to manipulate and endogenous -mRNA association. Finally, we demonstrate the effectiveness and specificity of modifier RNAs for regulating dependent mRNA stability in lysates of human peripheral blood mononuclear cells. We discuss our model and recent experimental findings demonstrating the effectivity of modifier RNAs in the context of the current research activities in the field of non-coding RNAs. We speculate that modifier RNAs might also exist in nature; if so, they present an additional regulatory layer for fine-tuning gene expression that could evolve rapidly, leaving no obvious traces in the genomic DNA sequences. Finally, we discuss the potential of modifier RNAs for applications in drug discovery and as tools in experimental biology.