Transcripts enriched in codons that trigger P‐site tRNA ‐mediated mRNA decay possess stable mRNA

Synonymous codon usage significantly influences mRNA stability in yeast by guiding mRNA decay during translation. The CCR4-NOT complex is central to this process, interacting with ribosomes when the A and E sites are unoccupied, a state that arises when a nonoptimal codon with low tRNA availability is at the A site. This triggers recruitment of decay factors, reducing the stability of transcripts enriched in such codons. In humans, codon-mediated mRNA decay is less well-understood. Recent research has identified a related but distinct mechanism called P-site tRNA-mediated decay (PTMD). Unlike yeast, human CCR4-NOT recruitment depends on specific arginine codons (CGG, CGA, or AGG) at the P site and slow decoding at the A site, allowing E-site vacancy and CNOT3-dependent binding. Through analysis of public datasets, we explored the characteristics of human transcripts enriched in PTMD codons. Interestingly, these codons are mostly found in transcripts with longer half-lives. This suggests that, rather than targeting already unstable mRNAs as in yeast, PTMD in humans selectively reduces the stability of otherwise long-lived transcripts, indicating a regulatory role distinct from the decay associated with codon usage.