Date of Award

Winter 2006

Project Type

Dissertation

Program or Major

Biochemistry

Degree Name

Doctor of Philosophy

First Advisor

Clyde L Denis

Abstract

The mRNA deadenylation process influences multiple aspects of protein synthesis and is known to be the major factor controlling mRNA decay rates. My data demonstrates that yeast PAB1 plays both positive and negative roles in controlling deadenylation, and I have identified particular regions of PAB1 involved in controlling different aspects of the mRNA degradative process. I have found that yeast PAB1 does not play a simple, obstructionist role in regulating CCR4 deadenylation. Instead, PAB1-PAB1 protein interactions, as mediated by the PAB1 proline-rich region (P domain) and the RRM1 domain, are required for the CCR4 deadenylase activity. The P and RRM1 domains were shown to mediate PAB1-PAB1 binding, suggesting that enhancing CCR4 function entails the rearrangement of the PAB1-mRNP structure. I have also established that PAB1 contacts to the poly (A) tail made by the RRM2 domain are critical to stabilizing the CCR4-NOT complex and promoting deadenylation. The C-terminal globular domain of PAB1 through its contacts to eRF3 is also required for CCR4 deadenylation. In contrast, the RRM3 domain of PAB1 inhibits deadenylation and decapping. mRNP structures involving the terminal PAB1 bound to poly (A) are also affected by RRM3 and control the end to deadenylation and apparently the commencement of decapping. These results indicate that PAB1 integrates and controls the transition from deadenylation to decapping and from a translationally competent state to an mRNA degradative state.

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