Translational Readthrough of Premature Termination Codons in a Therapeutic Context

Abstract

Coding sequences are defined between a start and a stop codon. The appearance of a nonsense mutation in a coding sequence creates a premature termination codon (PTC), preventing the correct production of the corresponding protein by interrupting translation and inducing the degradation of the transcript via the nonsense‐mediated mRNA decay (NMD) pathway. Over the past 10 years, there has been considerable interest in the possibility of suppressing in‐frame PTCs for therapeutic purposes. Indeed, some drugs have been shown to promote PTC readthrough by binding to mammalian ribosomes, thereby partially restoring the synthesis of a full‐length protein in cultured mammalian cells and animal models. This translational suppression strategy represents a promising therapeutic approach for genetic diseases and cancers due to a PTC. Key Concepts The stop codons in humans are UAA, UAG and UGA, and they are recognised by release factors. Near‐cognate tRNA‐binding codons display base pairing for only two of the three bases of the codon. Stop codon readthrough is the process by which the ribosome incorporates a near‐cognate tRNA at the stop codon.