| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2006: ¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2005: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Research Abstract |
In this study, we have investigated the initiation mechanism of mRNA decay. Control of mRNA decay is a fundamentally important step in determining the amount of protein produced from the mRNA by translation, and mRNA decay is intimately linked to and regulated by translation. In eukaryotes, decay of most mRNAs is initiated by shortening of the poly(A)-tail at the 3' end, referred to as deadenylation. Deadenylation is the first and rate-limiting step and also the most efficient step in controlling mRNA decay. Two major deadenylase complexes, Caf1-Ccr4 and Pan2-Pan3, play central roles in this process. However, the molecular mechanism triggering deadenylation remained elusive. We previously showed that translation termination factor eRF3 interacts with poly(A) binding protein (PABPC1) through its N-domain and that eRF3 regulates the initiation of mRNA decay at the poly(A) tail shortening step through the interaction with PABPC1 in a manner coupled to translation termination. Thus, transl
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ation termination triggers mRNA decay. Here we examined the mechanism of mRNA deadenylation and obtained evidence fir a molecular interplay between translation termination factor eRF3 and mRNA deadenylases. We have demonstrated that eRF3-mediated deadenylation is catalyzed by both of the two major mRNA deadenylase complexes, Caf1-Ccr4 and Pan2-Pan3, in yeast and humans. Interestingly, translation termination complex eRF1-eRF3, Pan2-Pan3 and Caf1-Ccr4 competitively bind to the PABC domain of PABPC1. In each complex, eRF3, Pan3 and Tob, respectively, mediate PABPC1-binding. The PAM2 motifs found in both eRF3 and the two deadenylase complexes are responsible both for their binding to PABPC1 and for mRNA deadenylation. The termination complex and the deadenylase complex are exchanged on PABPC1 in a translation-dependent manner. Recruitment of the two deadenylase complexes to PABPC1 leads to the activation of both enzymes. From these results, we suggest a mechanism of mRNA deadenylation by Pan2-Pan3 and Caf1-Ccr4 in cooperation with eRF3 and PABPC1. Less
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