Mechanisms of activation of human mRNA decapping

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DESCRIPTION (provided by applicant): Decapping is a central step in mRNA decay. The Dcp2 decapping complex is conserved throughout eukaryotes and is a key component of processing bodies (PBs), cytoplasmic granules of repressed messenger ribonucleoproteins (mRNPs). The mechanism by which mRNPs are modulated to allow decapping by the Dcp2 decapping complex is poorly understood. The objective of this proposal is to gain insights into how mRNPs are modified and remodeled in preparation for decapping, by addressing the following questions: 1) what is the role of the C-terminal RGG domain of the Lsm4 component of the Lsm1-7 complex in decapping and PB formation, 2) How does the Dcp2 decapping complex remodel the eIF4F cap-binding complex to gain access to the mRNA cap, and 3) what is the role of mRNA tailing in decapping and decay of endonucleolytically cleaved mRNA? Pursuing these questions should provide new insights into the mechanisms by which the Dcp2 decapping complex targets mRNAs for decapping and decay. This should provide new fundamental insights into the role of mRNP modification and remodeling in mRNA regulation. Relevance to Public Health The control of mRNA turnover is critical for proper regulation of gene expression, and its misregulation has been identified as a cause or a consequence of multiple human disorders. The studies described here are aimed at understanding the mechanisms by which mRNAs in human cells are modified and remodeled in preparation for decapping, a central step in mRNA turnover. This should provide fundamental new insights into mechanisms of mRNA regulation, which when deregulated can lead to disease.