Translational stop codons, UAA, UAG, and UGA, form an integral part of the universal genetic code. They are of significant interest today for their underlying fundamental role in terminating protein synthesis, but also for their potential utilisation for programmed alternative translation events. In diverse organisms, UAA has wide usage, but it is puzzling that the high fidelity UAG is selected against and yet UGA, vulnerable to suppression, is widely used, particularly in those archaeal and bacterial genomes with a high GC content. In canonical protein synthesis, stop codons are interpreted by protein release factors that structurally and functionally mimic decoding tRNAs and occupy the decoding site on the ribosome. The release factors make close contact with the decoding complex through multiple interactions. Correct interactions cause conformational changes resulting in new and enhanced contacts with the ribosome, particularly between specific bases in the mRNA and rRNA. The base following the stop codon (fourth or +4 base) may strongly influence decoding efficiency, facilitating alternative non-canonical events like frameshifting or selenocysteine incorporation. The fourth base is drawn into the decoding site with a compacted stop codon in the eukaryotic termination complex. Surprisingly, mRNA sequences upstream and downstream of this core tetranucleotide signal have a significant influence on the strength of the signal. Since nine bases downstream of the stop codon are within the mRNA channel, their interactions with rRNA, and r-proteins may affect efficiency. With this understanding, it is now possible to design stop signals of desired strength for specific applied purposes.

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