Determine the mechanisms by with inhibitory codons exert their effects
Project Collaborators:
Model of translation through internal CGA codon repeats. The ribosome stalls, continued
translation is blocked by ribosomal protein Asc1, ribosomal subunits are split, and the nascent
polypeptide is targeted for degradation by the ribosomal quality control complex (RQC).
A second project on codon-mediated inhibition is aimed at deducing the mechanism(s) by which inhibitory codons exert their effects on translation. Our analysis with CGA codons suggests that profound differences in translation efficiency can stem directly from decoding interactions in the ribosome. Thus, the study of codon-mediated inhibition is likely to provide insights into the workings of the ribosome, the RNA-protein machine responsible for converting genetic information into proteins, and possibly into mechanisms of ribosomal quality control. We have implicated three genes, two of which encode ribosomal proteins, in CGA-mediated inhibition, and defined molecular events that occur at CGA codon repeats. In a surprising turn of events, we discovered that loss of the ribosomal protein Asc1, the yeast homolog of human RACK1, not only improved translation through CGA codon repeats, but also allowed the ribosome to shift reading frames at a substantial rate. The molecular players and events involved in CGA-mediated frameshifting are under investigation, which may shed light on reading frame maintenance, a crucial function of the ribosome.