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Nonsense-containing mRNAs that accumulate in the absence of a functional nonsense-mediated mRNA decay pathway are destabilized rapidly upon its restitution

机译:在缺乏功能性无义介导的mRNa衰变途径时积累的含有无义酶的mRNa在其恢复原状后迅速失去稳定作用

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摘要

Nonsense-mediated mRNA decay (NMD) is a conserved proofreading mechanism that protects eukaryotic cells from the potentially deleterious effects of truncated proteins. Studies of Saccharomyces cerevisiae imply that NMD is a predominantly cytoplasmic decay pathway, while studies of mammalian systems suggest that decay of most substrate mRNAs may occur while they are still associated with the nucleus, possibly during a round of translation that occurs during their export to the cytoplasm. Complete entry of the latter mRNAs into the cytoplasm appears to render them immune to further NMD; i.e., they escape further susceptibility to this decay pathway. To determine if yeast cytoplasmic nonsense-containing mRNAs that evade decay are subsequently immune to NMD, we examined the consequences of placing each of the three UPF/NMD genes under the control of a galactose-inducible promoter. The decay kinetics of ADE2 and PGK1 nonsense-containing mRNAs were then analyzed when expression of UPF1, NMD2, or UPF3 was either repressed or subsequently induced. Results from these experiments demonstrated that activation of NMD caused rapid and immediate degradation of both substrate transcripts, with half-lives of both stable mRNA populations shortened to approximately 7 min. These findings make it unlikely that yeast nonsense-containing mRNAs can escape degradation by NMD and indicate that such mRNAs are available to this decay pathway at each round of translation.
机译:无意义介导的mRNA衰变(NMD)是一种保守的校对机制,可保护真核细胞免受截短蛋白的潜在有害作用。酿酒酵母的研究表明,NMD主要是细胞质的衰变途径,而对哺乳动物系统的研究表明,大多数底​​物mRNA的衰变可能在它们仍与细胞核结合的同时发生,可能是在它们输出到核糖核酸的过程中发生的一轮翻译中。细胞质。后者的mRNA完全进入细胞质似乎使它们对进一步的NMD免疫。也就是说,它们对这种衰变途径的敏感性更高。为了确定逃避衰变的酵母细胞质无义mRNAs随后是否对NMD免疫,我们检查了将三个UPF / NMD基因中的每一个置于半乳糖诱导型启动子控制下的后果。然后,当抑制或随后诱导UPF1,NMD2或UPF3的表达时,分析ADE2和PGK1无义mRNA的衰减动力学。这些实验的结果表明,NMD的激活导致两种底物转录本的快速和立即降解,两个稳定的mRNA群体的半衰期缩短至大约7分钟。这些发现使含酵母无义的mRNA不可能逃脱NMD的降解,并表明这种mRNA在每一轮翻译中都可用于该衰变途径。

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