Our overall goal is to elucidate the pathways and mechanisms involved in regulated mRNA stability and post-transcriptional control in general. These processes play a very important role in controlling gene expression related to cell growth and differentiation. Our approach is three-fold. First, we will expand our studies on nucleophosmin, a protein that is deposited on mRNAs as a novel polyadenylation mark, and determine its role in the coordination of gene expression. This work will involve the identification of auxiliary proteins involved in the polyadenylation mark, a determination of the requirements and mechanism of nucleophosmin deposition, the delineation of mRNA targets and a determination of the function(s) of nucleophosmin in post-transcriptional control. Second, we will perform a series of in vivo and in vitro assays to elucidate the full impact of CUG-BP, a regulator of poly(A) tail shortening in human cells, along with its target deadenylase enzyme PARN on the control of gene expression via the modulation of mRNA stability. Finally, we have identified a novel function of for a cytoplasmic Lsm complex in mRNA stability. The goal of the third aim of this proposal is to determine the underlying mechanism for Lsm-mediated stabilization of targeted mRNAs. In summary, these studies should provide new insights into the mechanisms and regulation of mRNA stability as well as post-transcriptional control in general. Given the impact of RNA biology on cellular growth control, these studies may well provide significant insights into the molecular basis of disease (e.g. cancer, myotonic dystrophy) and possibly improved strategies for molecular therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072481-14
Application #
8080874
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
1999-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2011
Total Cost
$345,104
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Jalkanen, Aimee L; Coleman, Stephen J; Wilusz, Jeffrey (2014) Determinants and implications of mRNA poly(A) tail size--does this protein make my tail look big? Semin Cell Dev Biol 34:24-32
Godwin, Alan R; Kojima, Shihoko; Green, Carla B et al. (2013) Kiss your tail goodbye: the role of PARN, Nocturnin, and Angel deadenylases in mRNA biology. Biochim Biophys Acta 1829:571-9
Wilusz, Carol J; Wilusz, Jeffrey (2013) Lsm proteins and Hfq: Life at the 3' end. RNA Biol 10:592-601
Geiss, Brian J; Wilusz, Jeffrey (2013) Ring around the Ro-sie: RNA-mediated alterations of PNPase activity. Cell 153:12-4
Moon, Stephanie L; Wilusz, Jeffrey (2012) In vitro transcription of modified RNAs. Methods Mol Biol 941:171-80
Neff, Ashley T; Lee, Ju Youn; Wilusz, Jeffrey et al. (2012) Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells. Genome Res 22:1457-67
Lee, Jerome E; Lee, Ju Youn; Trembly, Jarrett et al. (2012) The PARN deadenylase targets a discrete set of mRNAs for decay and regulates cell motility in mouse myoblasts. PLoS Genet 8:e1002901
Sagawa, Fumihiko; Ibrahim, Hend; Morrison, Angela L et al. (2011) Nucleophosmin deposition during mRNA 3' end processing influences poly(A) tail length. EMBO J 30:3994-4005
Dickson, Alexa M; Wilusz, Jeffrey (2011) Strategies for viral RNA stability: live long and prosper. Trends Genet 27:286-93
Lee, Jerome E; Lee, Ju Youn; Wilusz, Jeffrey et al. (2010) Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells. PLoS One 5:e11201

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