The control of biological processes, such as cellular growth and differentiation, is dependent on how the genetic material within a cell is expressed and regulated. Despite many recent observations that emphasize the importance of mRNA turnover in posttranscriptional gene regulation, little is known about the components of the mRNA turnover machinery and how their activity is modulated to give rise to the broad range of mRNA decay rates. We have described a pathway of mRNA decay in yeast shared by many, if not most, transcripts, in which poly(A) tail shortening triggers a nucleolytic cleavage at, or near, the cap structure (decapping), leading to 5' to 3' exonucleolytic degradation of the transcript. 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. In 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 by triggering extremely rapid mRNA decapping independent of poly(A) tail shortening. Given this importance, in this grant we focus on understanding the mechanism and control of decapping. We will use a combination of genetic and biochemical approaches to identify and determine the function of the gene products that catalyze and control the decapping reaction. This analysis should provide insight into the general principles of mRNA turnover, both in yeast and in more complex eukaryotes. The specific experimental aims are as follows: I. To identify mutations in genes required for mRNA decapping (termed MRT genes). II. To examine the functions and interactions of the MRT gene products in vivo. III. To analyze mRNA decapping in vitro.
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