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.
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