These investigations will focus on microRNA-mediated mRNA degradation in mammalian cells, with the goal of understanding the mechanism by which microRNAs expedite deadenylation as an early step in the degradation of their mRNA targets and the contribution of mRNA deadenylation and decay to gene regulation by microRNAs. Using cultured mammalian cells as model systems and molecular biological methods as analytical tools, we will investigate the proteins that contribute to microRNA-directed deadenylation, the manner in which they associate with one another, and the importance of those interactions for miRNA function. In addition, we will examine the impact of mRNA context on the degree to which microRNAs influence mRNA stability. Finally, we will explore the mechanism by which microRNAs identify their target sites in mRNA. The results of these studies should enhance our knowledge of a widespread mechanism of eukaryotic gene regulation that presently is poorly understood. This knowledge should ultimately be of value for understanding the etiology of diseases thought in some instances to be related to defects in microRNA function and for improving the efficacy of RNA interference as a medical therapy. Lay language statement: There is growing awareness that the hundreds of distinct microRNAs in human cells play key roles in gene regulation. Additional evidence suggests that microRNAs are important for viral infection and that defects in microRNA function can contribute to cancer and congenital abnormalities. The proposed research should eventually be of value for understanding the etiology of diseases related to microRNA function or dysfunction and for improving the efficacy of medical therapies based on small RNA molecules. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079477-02
Application #
7457856
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Bender, Michael T
Project Start
2007-09-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$288,150
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Richards, Jamie; Belasco, Joel G (2011) Ribonuclease J: how to lead a double life. Structure 19:1201-3
Savas, Jeffrey N; Ma, Bin; Deinhardt, Katrin et al. (2010) A role for huntington disease protein in dendritic RNA granules. J Biol Chem 285:13142-53
Piao, Xianghua; Zhang, Xue; Wu, Ligang et al. (2010) CCR4-NOT deadenylates mRNA associated with RNA-induced silencing complexes in human cells. Mol Cell Biol 30:1486-94
Belasco, Joel G (2010) All things must pass: contrasts and commonalities in eukaryotic and bacterial mRNA decay. Nat Rev Mol Cell Biol 11:467-78
Wu, Ligang; Belasco, Joel G (2008) Let me count the ways: mechanisms of gene regulation by miRNAs and siRNAs. Mol Cell 29:1-7
Wu, Ligang; Fan, Jihua; Belasco, Joel G (2008) Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Curr Biol 18:1327-32
Wu, Ligang; Belasco, Joel G (2008) Examining the influence of microRNAs on translation efficiency and on mRNA deadenylation and decay. Methods Enzymol 449:373-93