Talk on Saturday 09:45-10:00am submitted by Ying-Hsin Chen
The DEAD-box protein Dhh1p couples translation elongation to mRNA decay
Ying-Hsin Chen (Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106 ), Sophie Martin (Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106 ), Aditya Radhakrishnan (Program in Molecular Biophysics, Johns Hopkins University School of Medicine), Najwa AlHusaini (Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106 ), Rachel Green (Program in Molecular Biophysics, Johns Hopkins University School of Medicine), Jeff Coller (Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106 )
mRNA degradation regulates the steady-state levels of mRNAs. In eukaryotic cells, the major mRNA decay pathway is initiated by removal of 3’ polyA tail, followed by 5’ decapping and exonucleolytic digestion in a 5’ to 3’ direction. Our labs recently measured the global decay rate of mRNAs and found that mRNA stability correlates well with codon usage. The transcripts with a higher ratio of optimal codons are more stable compared to those composed with non-optimal codons. We also demonstrate that codon optimality impacts ribosome movement on mRNAs. How is translation elongation coupled to mRNA decay is the subject of our current work.
The DEAD-box protein Dhh1p is a known regulator of mRNA decapping and has suggested roles in translational control. In current study we demonstrate that Dhh1p is a sensor of codon optimality- consolidating an mRNA into decay if elongation rate is slow. First, we find that mRNAs whose translation elongation rate is slowed by inclusion of non-optimal codons are specifically degraded in a Dhh1p-dependent manner. We find that these effects on the mRNA decay are sensitive to the concentration of Dhh1p in the cell and the number of slowly moving ribosomes on an mRNA. Second, biochemical pull-downs show that Dhh1p is preferentially associated with mRNAs with suboptimal codon choice. Finally, over-expression of Dhh1p leads to the accumulation of ribosomes specifically on mRNAs with low codon optimality in ribosome profiling experiments.
These findings are consistent with a model that Dhh1p can bind on transcripts with slower translational elongation rate and act to promote mRNA decay.
1. Vladimir Presnyak, N. A.-H., Ying-Hsin Chen, Sophie Martin, Nathan, Morris, N. K., Sara Olson, David Weinberg, Kristian E. Baker, Brenton R. & Graveley, a. J. C. Codon optimality is a major determinant of mRNA stability. Cell (2015).
2. Sweet, T., Kovalak, C. & Coller, J. The DEAD-box protein Dhh1 promotes decapping by slowing ribosome movement. PLoS Biol (2012).
Keywords: Dhh1p, mRNA decay, codon optimality