AbstractRecognition of a stop codon by translation machinery as a sense codon results in translational readthrough instead of termination. This recoding process, termed stop codon readthrough (SCR) or translational readthrough, is found in all domains of life including mammals. The context of the stop codon, local mRNA topology, and molecules that interact with the mRNA region downstream of the stop codon determine SCR. The products of SCR can have localization, stability, and function different from those of the canonical isoforms. In this review, we discuss how recent technological and computational advances have increased our understanding of the SCR process in the mammalian system. Based on the known molecular events that occur during SCR of multiple mRNAs, we propose transient molecular roadblocks on an mRNA downstream of the stop codon as a possible mechanism for the induction of SCR. We argue, with examples, that the insights gained from the natural SCR events can guide us to develop novel strategies for the treatment of diseases caused by premature stop codons.This article is categorized under: Translation > Regulation