Understanding the interconnection between mRNA turnover and mRNA translation

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Abstract Messenger RNA (mRNA) decay is a critical step in the regulation of gene expression. mRNA decay in eukaryotes proceeds by removal of the 3' poly(A) tail (deadenylation) followed by removal of the 5' cap (decapping) then destruction of mRNA by 5' - 3' exonuclease digestion. This process of decay is intimately connected to mRNA translation, and a major goal of the field is to understand how translation interacts with decay to set decay rates. Our lab has made the important discovery that codon optimality is a critical determinant of decay rates transcriptome- wide. Further, we have identified the DEAD-box protein DHH1 as the sensor that detects slowed translation elongation associated with non-optimal codons and directs these messages to decapping and degradation. In light of this novel function for DHH1, this proposal seeks to understand the mechanism by which DHH1 senses slowed translation elongation and transmits this information to the decapping complex. The first aim is designed to understand how DHH1 interacts with the ribosome to sense slowed elongation. The second aim focuses on how DHH1 transmits a slowed elongation signal to the decapping complex. The third aim is to determine how deadenylation sensitizes mRNA to DHH1. Together, these aims will inform how DHH1 functions, thus providing insight into a wide range of gene expression events.