Normal termination codon (NTC) (NTC)

Normal termination codons (NTCs) are the specific nucleotide triplets—UAA, UAG, and UGA—within an mRNA sequence that signal the ribosome to cease polypeptide synthesis. When an NTC enters the ribosomal A site, it is recognized by eukaryotic release factors (eRF1 and eRF3) rather than transfer RNAs, triggering the release of the completed protein and the recycling of the ribosomal subunits [1][3]. In the context of drug development, NTCs are critical off-target sites for nonsense suppression therapies, such as ataluren or aminoglycosides, which are designed to promote the readthrough of premature termination codons (PTCs) caused by nonsense mutations [2]. A primary challenge in this therapeutic area is achieving high selectivity for PTCs over NTCs; excessive readthrough at NTCs can lead to the production of C-terminally extended proteins, which may cause proteotoxic stress or interfere with normal cellular functions [4][5]. Consequently, the interaction between small-molecule readthrough agents and the ribosomal machinery at the NTC is a focal point for assessing the safety and therapeutic index of translation-modulating drugs. Sources: [1] Alberts B, et al. Molecular Biology of the Cell. 6th edition. [2] Welch EM, et al. (2007). PTC124 targets genetic defects caused by nonsense mutations. Nature, 447(7140), 87-91. [3] Keeling KM, et al. (2014). Therapeutic strategies for nonsense mutations. Annual Review of Genomics and Human Genetics, 15, 371-420. [4] Linde L & Kerem B. (2008). Introducing stop codons: strategies and applications. Trends in Genetics, 24(5), 224-235. [5] Dabrowski M, et al. (2018). Translational Readthrough of Stop Codons in Cancer. International Journal of Molecular Sciences, 19(10), 2915.

Other names

Stop codonTermination codonNatural stop codonUAAUAGUGAEndogenous stop codon

Nonsense suppression agents bind to the decoding center of the ribosome (A-site) to decrease the fidelity of codon-anticodon recognition, potentially allowing near-cognate aminoacyl-tRNAs to compete with eukaryotic release factors (eRF1/eRF3) at the stop codon [1][2].