Molecular mechanisms of mRNA decay
Start date: Jul 1, 2009,
End date: Jun 30, 2013
All organisms require a reliable mechanism to turn genes on and off. This regulation of gene expression underlies cellular processes ranging from the response to environmental signals to the development of multi-cellular organisms and cell-cell communication. Understandably, the cell tightly controls gene expression at every step from DNA to protein. Recent work has given new insights into these control mechanisms and revealed dedicated pathways (including non sense mediated decay) that target mRNA for degradation, thereby efficiently turning genes off. Here, we propose to study the molecular mechanism that underlies the degradation of mRNA. Although many of the proteins involved have been identified, little is know about how the activity of the degradation machinery is regulated on an atomic level. We will study one of the core components, the DCP1:DCP2 decapping complex, that removes the protecting 5' cap structure from the mRNA. Specific question we will address range from the structure of the complex in solution, the catalytically important molecular motions and the way protein-protein or protein-RNA interactions can either activate or inhibit the activity of the decapping complex. We will use of nuclear magnetic resonance spectroscopy, to study these structure, motions and interactions. As these complexes involved can be of high molecular weight, we will exploit recently developed NMR methodology in concert with novel sample preparation techniques. In addition, we will extend our structural studies with in-vivo studies, where we can study the effect of mutations in residues that were found to be important for function. The interdisciplinary nature of this project and the use of a state-of-the-art structural approach promises to provide unique insights into the way cells regulate gene expression by removing mRNA from the transcriptional pool.
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