T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts
T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts
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DOI：
10.1093/emboj/21.1.125
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发表时间：
2002-01-15
期刊：
影响因子：
11.4
通讯作者：
Wilkinson, MF
中科院分区：
文献类型：
--
作者：
Gudikote, JP;Wilkinson, MF
无意义介导的衰变(NMD)RNA监测途径检测并降解含有提前终止密码子(PTCs)的mRNAs。T细胞受体(TCR)和免疫球蛋白转录本通常含有PTCs，这是正常发育过程中程序性DNA重排的结果，与其他已知的哺乳动物基因转录本相比，它们对无意义密码子的反应下调得更多。在这里，我们证明这不是由于启动子或细胞类型，而是由Vbeta8.1TCR-beta基因重排的VDJ外显子和紧邻内含子序列的调控序列控制的。将这些序列插入到异源基因中，可以引起对PTCS的强烈下调(30倍)，这表明这个区域足以触发强大的下调。来自TCR-beta家族另一个成员的重排Vbeta5.1外显子和侧翼内含子序列也引发了强烈的下调，这表明下调促进元件是TCR基因的一个保守特征。重要的是，我们发现Vbeta8.1下调调控元件是位置依赖的，因此当定位在PTC下游时，它无法发挥作用。据我们所知，这是第一类被发现的下行调控元件，作用于无意义密码子的上游。
The nonsense-mediated decay (NMD) RNA surveillance pathway detects and degrades mRNAs containing premature termination codons (PTCs). T-cell receptor (TCR) and immunoglobulin transcripts, which commonly harbor PTCs as a result of programmed DNA rearrangement during normal development, are down-regulated much more than other known mammalian gene transcripts in response to nonsense codons. Here, we demonstrate that this is not because of promoter or cell type but instead is directed by regulatory sequences within the rearranging VDJ exon and immediately flanking intron sequences of a Vbeta8.1 TCR-beta gene. Insertion of these sequences into a heterologous gene elicited strong down-regulation (>30-fold) in response to PTCs, indicating that this region is sufficient to trigger robust down-regulation. The rearranging Vbeta5.1 exon and the flanking intron sequences from another member of the TCR-beta family also triggered strong down-regulation, suggesting that down-regulatory-promoting elements are a conserved feature of TCR genes. Importantly, we found that the Vbeta8.1 down-regulatory-promoting element was position dependent, such that it failed to function when positioned downstream of a PTC. To our knowledge, this is the first class of down-regulatory elements identified that act upstream of nonsense codons.