Mechanisms Leading to the Loss of AUG Codon Function as a Translation Initiator

The AUG codon represents the canonical start site for translation initiation in eukaryotic cells, yet its proper function can be disrupted by a variety of regulatory mechanisms. In this review, conducted between April and June 2025, we comprehensively examined the most recent literature to identify key modulators that impair AUG-mediated initiation. These include suboptimal nucleotide contexts (e.g., weak Kozak consensus), RNA secondary structures adjacent to the start codon, and upstream open reading frames (uORFs) that compete with the primary initiation site. Furthermore, RNA-binding proteins and microRNAs were found to occlude ribosomal access, while variations in levels or activity of initiation factors—such as eIF1, eIF5, and related cofactors—can compromise start-site recognition. Collectively, these factors reduce the efficiency of 43S pre-initiation complex formation and accurate AUG selection, leading to decreased or misregulated protein synthesis with downstream effects on gene expression, stress response, development, and disease. By mapping structural, post-transcriptional, and initiation-factor–mediated regulatory pathways, this review highlights the multilayered control ordaining translation initiation. We also pinpoint gaps in existing knowledge and propose future research directions to enhance our understanding of AUG codon selection under both physiological and pathological contexts.