The NMD escape mechanism and its application in disease therapy

Nonsense-mediated mRNA decay (NMD) refers to the degradation of mRNA due to the presence of premature stop codon (PTC) on mRNA under pathological or physiological conditions. NMD is widely considered an mRNA-specific quality control process. Recently it was discovered that some PTCs do not trigger NMD in a variety of diseases - a process known as NMD escape; however, its exact mechanism remains unclear. At present, there are two widely accepted mechanistic hypotheses during NMD escape. The first is PTC read-through, in which protein translation undergoes PTC until the normal stop codon is encountered, producing a full-length protein. The second is translation reinitiation, in which protein translation recommences at the potential start codon downstream of PTC and terminates at the stop codon, producing an N-terminal truncated protein. Currently, an increasing number of drugs or small molecules that use PTC read-through have been successfully applied to treat nonsense variation-associated diseases. In this review, we summarize the NMD mechanism and discuss the application and progress in our understanding of NMD escape in disease therapy. This review should provide a useful framework to advance current understanding of the research and application of NMD escape.