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.

Public Health Relevance

mRNA degradation plays an important role in regulation of gene expression, the mis-regulation of which has been linked to multiple human disorders. mRNA decapping is a critical step in mRNA degradation;yet the mechanisms by which the mRNA decapping machineries are activated on target mRNAs remain poorly understood. The goal of this proposal is understand how human mRNA-protein complexes are modified and remodeled to allow activation of the Dcp2 decapping machinery.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM077243-05
Application #
8594106
Study Section
Special Emphasis Panel (ZRG1-GGG-L (02))
Program Officer
Bender, Michael T
Project Start
2007-08-13
Project End
2017-05-31
Budget Start
2013-07-08
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$286,739
Indirect Cost
$96,739
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Erickson, Stacy L; Lykke-Andersen, Jens (2011) Cytoplasmic mRNP granules at a glance. J Cell Sci 124:293-7
Damgaard, Christian Kroun; Lykke-Andersen, Jens (2011) Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR. Genes Dev 25:2057-68
Reznik, Boris; Lykke-Andersen, Jens (2010) Regulated and quality-control mRNA turnover pathways in eukaryotes. Biochem Soc Trans 38:1506-10
Mühlemann, Oliver; Lykke-Andersen, Jens (2010) How and where are nonsense mRNAs degraded in mammalian cells? RNA Biol 7:28-32
Franks, Tobias M; Singh, Guramrit; Lykke-Andersen, Jens (2010) Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell 143:938-50
Franks, Tobias M; Lykke-Andersen, Jens (2008) The control of mRNA decapping and P-body formation. Mol Cell 32:605-15