Our lab is exploring how translation itself can shape the stability and lifetime of mRNAs, a process that directly links codon usage to gene expression. In collaboration with the Mendell lab, we discovered a new co-translational decay pathway, termed P-site tRNA-mediated decay (PTMD), in which the presence of a specific subset of arginyl-tRNAs in the ribosomal P-site accelerates mRNA degradation during translation. Using molecular insights from cryo-electron microscopy, we identified key tRNA features that promote recruitment of CNOT3, a central subunit of the CCR4–NOT deadenylation complex responsible for initiating mRNA decay. We are now working to define the full molecular basis of this interaction, including the influence of tRNA base modifications and how targeted mutations can reprogram tRNAs to modulate CNOT3 recruitment. The discovery of PTMD reveals a new layer of gene regulation and has broad implications for understanding translation-linked gene regulation and for the design of RNA-based therapeutics.