The long term goal of our work is to understand the molecular mechanisms that control mRNA stability. Despite many recent observations that emphasize the importance of mRNA turnover in post- transcriptional gene regulation, little is known about how this process modulated to give rise to the broad range of mRNA decay rates. We have described the major pathway of mRNA decay in yeast wherein poly(A) tail shortening triggers decapping, leading to 5' to 3' exonucleolysis. Decapping is a key step in this mechanism because it is the step that induces degradation of the mRNA, and it is the site of numerous control inputs. For example the major effect of the poly(A) tail on mRNA decay is through an inhibition of decapping. I addition, specific sequences that modulate mRNA decay rate can do so by affecting the rates of decapping. Moreover, a specialized decay pathway that degrades aberrant transcripts works triggering extremely rapid mRNA decapping independent of poly(A) tail shortening. Given this importance, we have focused on understanding the mechanisms of mRNA decapping. In the past funding period, we identified a number of interacting proteins that comprise the mRNA decapping machinery including the decapping enzyme (Dcp1p), a required positive regulator (Dcp2p), and a complex of Lsm proteins, which are related to the Sm proteins that are core components of snRNPs. In this grant, we will use a combination of genetic and biochemical approaches to determine the functions of these proteins in mRNA decapping. This analysis will provide insight into the mechanisms of mRNA turnover, both in yeast and in more complex eukaryotes. The specific experimental aims are: I. TO DETERMINE THE FUNCTION OF THE Dcp2 PROTEIN. II. TO EXAMINE THE SIGNIFICANCE OF INTERACTIONS BETWEEN THE mRNA DECAY PROTEINS. III. TO EXAMINE THE NATURE AND SIGNIFICANCE OF INTERACTIONS BETWEEN THE LSM COMPLEX AND mRNA. IV. TO EXAMINE IF THE LSM PROTEINS FUNCTION IN TRANSLATION.
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