Alternatively spliced T-cell receptor transcripts are up-regulated in response to disruption of either splicing elements or reading frame
Alternatively spliced T-cell receptor transcripts are up-regulated in response to disruption of either splicing elements or reading frame
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DOI：
10.1074/jbc.m704372200
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发表时间：
2007-10-12
影响因子：
4.8
通讯作者：
Wilkinson, Miles F.
中科院分区：
文献类型：
--
作者：
Chang, Yao-Fu;Chan, Wai-Kin;Wilkinson, Miles F.
无义突变产生提前终止密码子(PTCs)，导致截短蛋白的产生，其中一些具有有害的功能获得或显性负活性。保护细胞免受这种异常蛋白影响的是无感觉中介衰变(NMD)，这是一种RNA监测途径，可以降解携带PTCs的转录本。对无义突变的第二反应是跳过PTC的选择性剪接转录本的上调。这种无意义相关的改变剪接(NAS)反应具有挽救蛋白质功能的潜力，但其触发机制一直存在争议。一些研究表明，与NMD一样，NAS是由于无义突变扰乱阅读框架而触发的，而另一些研究表明，NAS是在无义突变扰乱外显子剪接增强子(ESES)时触发的。利用T细胞受体-β(TCRβ)，它自然地以高频获得PTCs，我们提供了两种机制作用于单一类型的mRNA的证据。破坏共识ESE位点的突变上调了选择性剪接的TCRβ转录本，该转录本跳过了突变，而不受阅读框架中断和NMD因子UPF1的影响。相反，没有破坏共识ESE位点的阅读框架干扰突变引发了依赖于UPF1的选择性剪接TCRβ转录本的上调。阅读框的恢复阻止了这种上调。我们的结果表明，信使核糖核酸对无义突变的反应取决于其背景。
Nonsense mutations create premature termination codons ( PTCs), leading to the generation of truncated proteins, some of which have deleterious gain-of-function or dominant-negative activity. Protecting cells from such aberrant proteins is nonsensemediated decay ( NMD), an RNA surveillance pathway that degrades transcripts harboring PTCs. Asecond response to nonsense mutations is the up-regulation of alternatively spliced transcripts that skip the PTC. This nonsense-associated altered splicing ( NAS) response has the potential to rescue protein function, but the mechanism by which it is triggered has been controversial. Some studies suggest that, like NMD, NAS is triggered as a result of nonsense mutations disrupting reading frame, whereas other studies suggest thatNASis triggered when nonsense mutations disrupt exonic splicing enhancers ( ESEs). Using T-cell receptor-beta( TCR beta), which naturally acquires PTCs at high frequency, we provide evidence that both mechanisms act on a single type of mRNA. Mutations that disrupt consensus ESE sites up-regulated an alternatively spliced TCR beta transcript that skipped the mutations independently of reading frame disruption and the NMD factor UPF1. In contrast, reading frame disrupting mutations that did not disrupt consensus ESE sites elicited UPF1-dependent up-regulation of the alternatively spliced TCR beta transcript. Restoration of reading frame prevented this up-regulation. Our results suggest that the response of an mRNA to a nonsense mutation depends on its context.