NMD逃逸机制及其在疾病治疗中的应用

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。

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.