Physiological UGA stop codon (UGA)

Physiological UGA stop codons are specific nucleotide triplets (Uracil-Guanine-Adenine) located at the 3' end of the coding sequence in endogenous messenger RNAs, serving as a primary signal for the termination of protein translation. These codons are recognized by eukaryotic release factors, primarily eRF1, which triggers the hydrolysis of the ester bond between the polypeptide chain and the tRNA, effectively ending protein synthesis (Source: NIH/NCBI Bookshelf). While their primary role is termination, UGA codons can also be recoded to incorporate selenocysteine in the presence of specific RNA structural elements, making them essential for the production of selenoproteins (Source: Papp et al., 2007, PubMed). In the context of pharmacology, physiological UGA codons are not intended therapeutic targets but represent critical sites of potential off-target activity for "readthrough" or "nonsense-suppression" drugs like Ataluren and aminoglycosides. These drugs are designed to bypass premature termination codons (PTCs) caused by nonsense mutations in genetic diseases like Duchenne muscular dystrophy; however, a significant safety concern is the unintended readthrough of physiological stop codons, which can result in the production of C-terminally extended proteins with unknown functional or toxicological consequences (Source: Keeling et al., 2014, PubMed). Achieving selectivity for PTCs over physiological stop codons is a major hurdle in the development of safe nonsense-suppression therapies (Source: EMA, Translarna Assessment Report).

Other names

Opal codonUGA termination codonTGA codonNatural stop codon

Induction of translational readthrough by promoting the insertion of a near-cognate aminoacyl-tRNA at the stop codon site, allowing the ribosome to bypass the termination signal.