Our goal is to elucidate the pathways and mechanisms involved in general and regulated mRNA stability, a process that plays an important role in controlling aspects of gene expression related to cell growth and differentiation. Our approach to this goal will largely center around a novel in vitro system we have developed and successfully exploited in the past that faithfully reproduces aspects of both general and regulated mRNA stability on exogenous RNA substrates. First, by strategic placement of structural blocks into RNA substrates, we will determine the in vivo pathways involved in the degradation of the body of the mRNA following deadenylation. Second, we will use an in vitro approach to determine how deadenylation of mRNA substrates is differentially regulated by distinct classes AU-rich elements. Third, we will determine how non-AU-rich elements, namely the pyrimidine-rich element of the important immune modulator CD154 and the U-rich element of the c-jun proto-oncogene, function to regulate mRNA stability. Finally, we have recently identified a complex of 3 proteins that assembles on the 3' UTR of an mRNA in a polyadenylation dependent manner. We will investigate the identity and functional significance of these proteins in a variety of post-transcriptional processes. These studies on the mechanisms and regulation of mRNA stability will have a profound impact on our appreciation of molecular mechanisms of cellular growth control, as well as providing insights into the molecular basis of disease (e.g. cancer) and possibly improved strategies for gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072481-09
Application #
7086373
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Rhoades, Marcus M
Project Start
1999-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
9
Fiscal Year
2006
Total Cost
$297,344
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
Russo, Joseph; Mundell, Cary T; Charley, Phillida A et al. (2018) Engineered viral RNA decay intermediates to assess XRN1-mediated decay. Methods :
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

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