mRNA turnover is a key step in regulation of gene expression. Its mis-regulation has been linked to a range of human disorders. The long-term goal of my laboratory is to understand the mechanism and regulation of mRNA turnover in humans. Removal of the mRNA 5' cap by the process of decapping is an important step in mRNA turnover. Recent evidence has shown that the protein complex responsible for decapping co-localizes with other factors involved in degradation of mRNA from the 5' end in sub-cytoplasmic foci termed processing bodies. Moreover, compelling data shows that processing bodies are active in mRNA decay. This suggests that mRNA decay can be a localized process. Here we will test the role of human processing bodies in three specific mRNA decay processes that play a key role in human gene expression and disease: All-rich element (ARE)-mediated mRNA decay, nonsense-mediated decay (NMD) and mRNA decay triggered by micro (mi)RNAs. We will employ in situ hybridization, indirect immunofluorescence, co- immunoprecipitation and mRNA decay assays to test how these mRNA decay pathways interface with processing bodies. In addition, we will test if catalytic components of PBs are targeted for proteolysis when localized outside of PBs where they may stimulate promiscuous RNA decay. These experiments are aimed at addressing the following questions: i) How are unstable mRNAs targeted to processing bodies and ii) why are mRNA decay enzymes concentrated in PBs rather than throughout the cytoplasm? This proposal is relevant to public health because mis-regulation of the degradation of protein-encoding mRNAs has been linked to a range of human disorders. Understanding the mechanism behind mRNA turnover will help develop strategies to fight such diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM077243-01A2
Application #
7316347
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Rhoades, Marcus M
Project Start
2007-08-13
Project End
2011-05-31
Budget Start
2007-08-13
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$218,837
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Wang, Ying; Arribas-Layton, Marc; Chen, Yifang et al. (2015) DDX6 Orchestrates Mammalian Progenitor Function through the mRNA Degradation and Translation Pathways. Mol Cell 60:118-30
Erickson, Stacy L; Corpuz, Elizabeth O; Maloy, Jeffrey P et al. (2015) Competition between Decapping Complex Formation and Ubiquitin-Mediated Proteasomal Degradation Controls Human Dcp2 Decapping Activity. Mol Cell Biol 35:2144-53
Hausburg, Melissa A; Doles, Jason D; Clement, Sandra L et al. (2015) Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. Elife 4:e03390
Reznik, Boris; Clement, Sandra L; Lykke-Andersen, Jens (2014) hnRNP F complexes with tristetraprolin and stimulates ARE-mRNA decay. PLoS One 9:e100992
Arribas-Layton, Marcos; Wu, Donghui; Lykke-Andersen, Jens et al. (2013) Structural and functional control of the eukaryotic mRNA decapping machinery. Biochim Biophys Acta 1829:580-9
Erickson, Stacy L; Lykke-Andersen, Jens (2011) Cytoplasmic mRNP granules at a glance. J Cell Sci 124:293-7

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