Physiological stop codon (PSC)

Physiological stop codons (PSCs) are the naturally occurring nucleotide triplets (UAA, UAG, or UGA) that signal the end of a coding sequence in wild-type messenger RNA (mRNA). Their primary biological role is to recruit eukaryotic release factors (eRF1 and eRF3) to the ribosome, which triggers the hydrolysis of the peptidyl-tRNA bond and the release of the completed polypeptide chain (Schueren & Thoms, 2016). In the context of drug development, PSCs are not therapeutic targets but are critical off-targets for nonsense suppression therapies, such as ataluren or aminoglycosides, which are designed to promote the readthrough of premature stop codons (PTCs) caused by nonsense mutations (Keeling et al., 2014). A major challenge in this field is achieving selectivity for PTCs over PSCs; unintended readthrough at PSCs can lead to the synthesis of proteins with C-terminal extensions. These aberrant proteins may undergo misfolding, lose their original biological function, or exert proteotoxic effects on the cell, potentially leading to systemic toxicity (Linde & Kerem, 2008).

Other names

Normal termination codonNTCNatural stop codonWild-type stop codonCanonical stop codon

Translational readthrough (suppression of termination)