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REVIEW ARTICLE

Mechanisms leading to the loss of the AUG codon function as a translation initiator: A review

Thualfiqar Ghalib Turki1* ,  Arif Abbas Ghayyib2
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1 Department of Laboratory Techniques, Faculty of Medical Technologies, Islamic University of Najaf, Najaf, Iraq
2 Department of Criminal Evidence Sciences, Faculty of Medical Sciences, Jabir Ibn Hayyan University for Medical and Pharmaceutical Sciences, Kufa, Najaf, Iraq
GPD, 025350065 https://doi.org/10.36922/GPD025350065
Received: 30 August 2025 | Revised: 20 April 2026 | Accepted: 20 April 2026 | Published online: 22 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

The AUG codon represents the canonical start site for translation initiation in eukaryotic cells; however, its accurate recognition is governed by a complex network of regulatory mechanisms. In this review, we comprehensively examined recent literature to identify key determinants that impair AUG-mediated initiation. These include suboptimal nucleotide contexts such as weak Kozak consensus sequences, RNA secondary structures proximal to the start codon, and upstream open reading frames that compete with the primary initiation site. In addition, RNA-binding proteins and microRNAs can restrict ribosomal access, while alterations in initiation factor availability or activity (including eukaryotic translation initiation factor 1, eukaryotic translation initiation factor 5, and associated cofactors) further modulate start codon selection fidelity. Collectively, these elements influence the assembly and stability of the 43S pre-initiation complex, thereby affecting the efficiency and accuracy of AUG recognition and ultimately shaping translational output. Beyond the canonical eukaryotic scanning mechanism, bacterial translation initiation relies on the Shine–Dalgarno sequence to position the ribosome at the correct start codon, highlighting fundamental mechanistic differences while underscoring a shared requirement for precise start site selection. Together, these regulatory layers contribute to translational plasticity, with implications for gene expression control, stress adaptation, development, and disease. This review also identifies current gaps in understanding and proposes future directions to further elucidate how start codon selection is coordinated under physiological and pathological conditions.

Graphical abstract
Keywords
AUG initiation
Kozak context
Upstream open reading frames
Eukaryotic translation initiation factor 1/5
RNA structure
Post-transcriptional regulation
Funding
None.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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