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 ?eld 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 identi?ed 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 ?rst 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 i s 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.
Importance to Human Health RNA communicates the genetic information found within DNA. In order for cells to function appropriately, signals communicated by RNA must be turned on and off. This grant focuses on how RNA signals are turned off. Failure to regulate RNA appropriately has devastating cellular consequences that can lead to cancer, neurological defects, and embryological malformations.
| Arango, Daniel; Sturgill, David; Alhusaini, Najwa et al. (2018) Acetylation of Cytidine in mRNA Promotes Translation Efficiency. Cell 175:1872-1886.e24 |
| Burow, Dana A; Martin, Sophie; Quail, Jade F et al. (2018) Attenuated Codon Optimality Contributes to Neural-Specific mRNA Decay in Drosophila. Cell Rep 24:1704-1712 |
| Webster, Michael W; Chen, Ying-Hsin; Stowell, James A W et al. (2018) mRNA Deadenylation Is Coupled to Translation Rates by the Differential Activities of Ccr4-Not Nucleases. Mol Cell 70:1089-1100.e8 |
| Hanson, Gavin; Alhusaini, Najwa; Morris, Nathan et al. (2018) Translation elongation and mRNA stability are coupled through the ribosomal A-site. RNA 24:1377-1389 |
