PDF(Pubmed)
Abstract：
Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay. We find that Upf1 binds poorly translated and untranslated ORFs, which are associated with a higher decay rate, including mRNAs with uORFs and those with exposed ORFs after stop codons. Our study emphasizes Upf1\'s converging role in surveilling mRNAs with exposed ORFs that are poorly translated, such as mRNAs with long ORFs, ORF-like 3\' UTRs, and mRNAs containing uORFs. We propose that Upf1 regulation of poorly/untranslated ORFs provides a unifying mechanism of surveillance in regulating mRNA stability and homeostasis in an exon-junction complex (EJC)-independent nonsense-mediated decay (NMD) pathway that we term ORF-mediated decay (OMD).
摘要：
转录后mRNA调控塑造基因表达，然而，顺式元件和mRNA翻译界面如何调节mRNA的稳定性却知之甚少。我们发现翻译启动的力量，上游开放阅读框架(uORF)内容，密码子最优性，AU丰富的元素，microRNA结合位点,和开放阅读框（ORF）长度组合功能以调节mRNA的稳定性。机器学习分析确定ORF长度是调节mRNA衰变的最重要的保守特征。我们发现Upf1绑定翻译不好和未翻译的ORF，它们与更高的衰变率有关，包括具有uORF的mRNA和终止密码子后具有暴露ORF的mRNA。我们的研究强调了Upf1在监控具有翻译不良的暴露ORF的mRNA中的融合作用，例如具有长ORF的mRNA，ORF-like3\'UTR,和含有uORF的mRNA。我们建议Upf1调节不良/未翻译的ORF提供了一种统一的监测机制，可以调节外显子连接复合物（EJC）独立的无义介导的衰变（NMD）途径中的mRNA稳定性和稳态，我们将其称为ORF介导的衰变（OMD）。
