Endogenous stop codon (ESC)

Endogenous stop codons (ESCs), also referred to as normal termination codons (NTCs), are the specific nucleotide triplets (UAA, UAG, or UGA) that signal the end of protein synthesis in wild-type messenger RNA. These codons are recognized by eukaryotic release factors, which trigger the release of the nascent polypeptide chain and the disassembly of the translation complex (Alberts et al., 2002). While not a therapeutic target in the traditional sense, ESCs are critical off-targets for nonsense suppression therapies, such as ataluren and aminoglycosides, which are designed to induce readthrough of premature stop codons (PTCs) in genetic diseases like Duchenne muscular dystrophy (Linde & Kerem, 2008). The pharmacological induction of readthrough at ESCs can result in the production of C-terminally extended proteins, which may lead to proteotoxicity, protein misfolding, or altered cellular localization (Keeling et al., 2014). Consequently, the selectivity of readthrough agents for PTCs over ESCs is a primary safety consideration and a major hurdle in the development of translation-based therapeutics (Haas et al., 2015). Monitoring for C-terminal extensions is often used as a biomarker for the off-target effects of these drugs.

Other names

Normal termination codonNTCNatural stop codonWild-type stop codon

Nonsense suppression agents reduce the fidelity of the ribosome at stop codons, allowing the incorporation of a near-cognate amino acid and subsequent translational readthrough.