Autoregulation of the nonsense-mediated mRNA decay pathway in human cells.
Autoregulation of the nonsense-mediated mRNA decay pathway in human cells.
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DOI：
10.1261/rna.030247.111
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发表时间：
2011-12
期刊：
影响因子：
4.5
通讯作者：
H. Yepiskoposyan;Florian Aeschimann;D. Nilsson;M. Okoniewski;O. Mühlemann
中科院分区：
文献类型：
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作者：
H. Yepiskoposyan;Florian Aeschimann;D. Nilsson;M. Okoniewski;O. Mühlemann
无意义介导的信使核糖核酸衰变(NMD)传统上被描述为一种通过截断开放阅读框架(ORF)降解mRNAs的质量控制机制。然而，同时清楚的是，NMD也参与了许多生理mRNAs的转录后基因调控。为了鉴定内源性NMD底物mRNAs并分析使它们对NMD敏感的特征，我们对缺失NMD因子UPF1、SMG6或SMG7的人细胞进行了转录组谱分析。结果表明，与人类mRNAome相比，被NMD去除上调的mRNAs具有更长的中位数3‘-UTR长度，并富含3’-UTR内含子和uORF。有趣的是，大多数编码NMD因子的mRNAs都在NMD敏感的转录本中，这意味着NMD过程是自动调节的。这些mRNAs都具有长的3‘UTRs，其中一些含有uORFs。通过报告基因分析，我们证明UPF1、SMG5和SMG7mRNAs的长3‘UTRs是这些mRNAs诱发NMD的主要特征，提示长3’UTRs可能是NMD的频繁触发因素。
Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 3'-UTR length compared with that of the human mRNAome and were also enriched for 3'-UTR introns and uORFs. Intriguingly, most mRNAs coding for NMD factors were among the NMD-sensitive transcripts, implying that the NMD process is autoregulated. These mRNAs all possess long 3' UTRs, and some of them harbor uORFs. Using reporter gene assays, we demonstrated that the long 3' UTRs of UPF1, SMG5, and SMG7 mRNAs are the main NMD-inducing features of these mRNAs, suggesting that long 3' UTRs might be a frequent trigger of NMD.