PDF(Pubmed)
Abstract：
Nonsense-mediated mRNA decay (NMD) is a quality control pathway in eukaryotes that continuously monitors mRNA transcripts to ensure truncated polypeptides are not produced. The expression of many normal mRNAs that encode full-length polypeptides is also regulated by this pathway. Such transcript surveillance by NMD is intimately linked to translation termination. When a ribosome terminates translation at a normal termination codon, NMD is not activated, and mRNA can undergo repeated rounds of translation. On the other hand, when translation termination is deemed abnormal, such as that on a premature termination codon, it leads to a series of poorly understood events involving the NMD pathway, which destabilizes the transcript. In this review, we summarize our current understanding of how the NMD machinery interfaces with the translation termination factors to initiate NMD. We also discuss a variety of cis-acting sequence contexts and trans-acting factors that can cause readthrough, ribosome reinitiation, or ribosome frameshifting at stop codons predicted to induce NMD. These alternative outcomes can lead to the ribosome translating downstream of such stop codons and hence the transcript escaping NMD. NMD escape via these mechanisms can have wide-ranging implications on human health, from being exploited by viruses to hijack host cell systems to being harnessed as potential therapeutic possibilities to treat genetic diseases.
摘要：
无义介导的mRNA衰变（NMD）是真核生物中的质量控制途径，可连续监测mRNA转录物以确保不产生截短的多肽。许多编码全长多肽的正常mRNA的表达也受该途径调节。NMD的这种转录本监测与翻译终止密切相关。当核糖体在正常终止密码子终止翻译时，NMD未激活，和mRNA可以经历重复的翻译轮。另一方面,当翻译终止被视为异常时，比如在提前终止密码子上，它导致了一系列涉及NMD途径的鲜为人知的事件，这会破坏笔录的稳定性。在这次审查中,我们总结了我们目前对NMD机制如何与翻译终止因素相互作用以启动NMD的理解。我们还讨论了各种顺式作用序列上下文和可能导致阅读的反式作用因素，核糖体的重新起始,或核糖体移码在预测诱导NMD的终止密码子处。这些替代结果可导致核糖体在此类终止密码子的下游翻译，从而导致转录物逃逸NMD。NMD通过这些机制逃逸可能对人类健康产生广泛影响，从被病毒利用到劫持宿主细胞系统，到被用作治疗遗传疾病的潜在治疗可能性。
