Synonymous codon usage: Regulator of mRNA stability & translation initiation

Abstract: Synonymous codons can reduce gene expression, but the mechanisms remain unclear. Using reporter assays in human cells, I found that nonoptimal codons lower protein levels mainly by reducing translation initiation-not just by degrading mRNA. Imaging revealed that these transcripts attract fewer ribosomes and bind less to key initiation factors eIF4E and eIF4G. This repression occurs without mRNA decay and independently of CNOT3. These findings reveal a new mechanism of codon-mediated regulation and help explain why transcript levels often don't predict protein abundance.