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.
无义介导的mRNA降解(nonsense-mediated mRNA decay, NMD)是指在病理或正常生理情况下mRNA上出现了提前终止密码子(premature termination codon, PTC),从而导致mRNA降解。它是一种广泛存在的mRNA质量监控机制。近年来,在多种疾病中发现某些PTC并未触发NMD,这种现象被称为NMD逃逸(NMD escape),然而其确切机制尚不十分清楚。目前公认的两个学说为:(1) PTC通读,即蛋白的翻译可以顺利通过PTC直至正常的终止密码子,产生全长蛋白;(2)翻译的重新启动,即蛋白翻译在PTC下游的潜在起始点重新开始直至终止密码子,产生N端截短蛋白。目前,通过利用PTC通读,越来越多的药物或小分子已被成功用于无义变异相关疾病的治疗。本文主要综述了NMD逃逸的机制及其在疾病治疗中的应用和进展,以期为进一步了解NMD逃逸及其相关应用概况提供参考。.