Pushing the limits of the scanning mechanism for initiation of translation

By M. Kozak. Gene, 2002

929 citations recorded by the source corpus.

Selection of the translational initiation site in most eukaryotic mRNAs appears to occur via a scanning mechanism which predicts that proximity to the 5′ end plays a dominant role in identifying the start codon. This ‘position effect’ is seen in cases where a mutation creates an AUG codon upstream from the normal start site and translation shifts to the upstream site. The position effect is evident also in cases where a silent internal AUG codon is activated upon being relocated closer to the 5′ end. Two mechanisms for escaping the first-AUG rule – reinitiation and context-dependent leaky scanning – enable downstream AUG codons to be accessed in some mRNAs. Although these mechanisms are not new, many new examples of their use have emerged. Via these escape pathways, the scanning mechanism operates even in extreme cases, such as a plant virus mRNA in which translation initiates from three start sites over a distance of 900 nt. This depends on careful structural arrangements, however, which are rarely present in cellular mRNAs. Understanding the rules for initiation of translation enables understanding of human diseases in which the expression of a critical gene is reduced by mutations that add upstream AUG codons or change the context around the AUGSTART codon. The opposite problem occurs in the case of hereditary thrombocythemia: translational efficiency is increased by mutations that remove or restructure a small upstream open reading frame in thrombopoietin mRNA, and the resulting overproduction of the cytokine causes the disease. This and other examples support the idea that 5′ leader sequences are sometimes structured deliberately in a way that constrains scanning in order to prevent harmful overproduction of potent regulatory proteins. The accumulated evidence reveals how the scanning mechanism dictates the pattern of transcription – forcing production of monocistronic mRNAs – and the pattern of translation of eukaryotic cellular and viral genes.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4961e052af93fa9728a6b0b04edd72361298b53b

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Citations in the corpus

Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria (2004, background): “Parasites that express VSA PAM -type antigens on the IE surface selectively transcribe an unusually structured var gene ( var2csa ) at high levels (8), but the presence of a short open reading frame upstream of the var2csa initiation codon (9, 10) has raised concern that var2csa mRNA may not be tran”
AceView: a comprehensive cDNA-supported gene and transcripts annotation (2006, background): “But it is difficult to conceive how the ribosomes would be aware of these rules, instead of following the scanning mechanism experimentally established by Kozak [14].”
A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. (2008, background): “2003) generates a 3-kb 5 -UTR mRNA, which is unlikely to be suitable for this mechanism since its length inhibits efficient ribosome scanning (Kozak 2002).”
Molecular mechanisms of translational control (2004, background): “Several studies imply that the 43S pre-initiation complex scans along the 5′ UTR until it reaches and identifies the initiation codon 10 .”
Regulation of translation via mRNA structure in prokaryotes and eukaryotes. (2005, background): “The scanning mechanism of initiation (Kozak, 2002a) postulates that the 40S ribosomal subunit enters at the 5′ end of the mRNA and migrates linearly until it encounters the first AUG codon, which is recognized by base-pairing with the anticodon in Met-tRNAi (Cigan et al., 1988a). eIF2, the factor…”