mRNA turnover plays an essential role in gene expression. Specific cell signals can transiently stabilize unstable mRNAs or destabilize stable mRNAs to regulate protein expression. Misregulation of mRNA turnover is associated with a range of human diseases. Two important mRNA decay processes are those of nonsense-mediated decay (NMD), a process that detects and degrades mRNAs that fail to encode full-length protein, and AU-rich element (ARE)-mediated decay, which is responsible for the rapid decay of mRNAs with AREs. These are often found in the 3'UTR of mRNAs encoding proto-oncogenes, cytokines and growth factors. Both of these mRNA decay pathways trigger rapid mRNA deadenylation, an important often regulatory step in mRNA decay. With the long-term goal of understanding how mRNA decay is regulated in gene expression and disease, we have identified ten putative human deadenylases using a bioinformatics approach. These will be studied by: 1) testing their in vitro deadenylation activity, and 2) by studying their role in nonsense-mediated decay and in 3) ARE-mediated decay in human tissue culture cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066811-05
Application #
7384444
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Bender, Michael T
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$233,234
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
Clement, Sandra L; Scheckel, Claudia; Stoecklin, Georg et al. (2011) Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol Cell Biol 31:256-66
Clement, Sandra L; Lykke-Andersen, Jens (2008) A tethering approach to study proteins that activate mRNA turnover in human cells. Methods Mol Biol 419:121-33
Franks, Tobias M; Lykke-Andersen, Jens (2007) TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes Dev 21:719-35
Wagner, Eileen; Clement, Sandra L; Lykke-Andersen, Jens (2007) An unconventional human Ccr4-Caf1 deadenylase complex in nuclear cajal bodies. Mol Cell Biol 27:1686-95
Lykke-Andersen, Jens; Wagner, Eileen (2005) Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev 19:351-61
Kedersha, Nancy; Stoecklin, Georg; Ayodele, Maranatha et al. (2005) Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 169:871-84