Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila
Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila
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DOI：
10.1038/nature02559
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发表时间：
2004-06-03
期刊：
影响因子：
64.8
通讯作者：
Izaurralde, E
中科院分区：
文献类型：
--
作者：
Gatfield, D;Izaurralde, E
在真核细胞中，含有过早终止密码子（ptc）的信使rna通过一种被称为无义介导的mRNA衰变（NMD）的保守转录后机制迅速降解（1,2），这阻止了可能对细胞有害的截断蛋白的合成（1,2）。在酵母和哺乳动物中的研究表明，通过这种途径的降解可以发生在信息的5‘端（包括脱盖和XRN1的5’到3‘外核溶解消化）或3’端（通过加速死基化和外泌体介导的3‘到5’衰变）（3-9）。在这里，我们表明，与预期相反，果蝇中含有ptc的信息的降解是由无义密码子附近的核内溶分裂(s)引发的。产生的5‘片段通过外泌体的外核溶解消化迅速降解，而3’片段则被XRN1降解。这种衰减途径在几种含有ptc的报告基因以及一种由NMD自然调节的内源性mRNA中得到了证实。我们得出的结论是，尽管NMD机制存在保护，但果蝇中含有ptc的转录本的降解机制与酵母和哺乳动物中的降解机制有很大不同（3,6,7）。
In eukaryotic cells, messenger RNAs harbouring premature termination codons (PTCs) are rapidly degraded by a conserved post-transcriptional mechanism referred to as nonsense-mediated mRNA decay (NMD)(1,2), which prevents the synthesis of truncated proteins that could be deleterious for the cell(1,2). Studies in yeast and mammals indicate that degradation by means of this pathway can occur from both the 5' end of the message (involving decapping and 5'-to-3' exonucleolytic digestion by XRN1) or the 3' end (through accelerated deadenylation and exosome-mediated 3'-to-5' decay)(3-9). Here we show that, contrary to expectation, degradation of PTC-containing messages in Drosophila is initiated by endonucleolytic cleavage(s) in the vicinity of the nonsense codon. The resulting 5' fragment is rapidly degraded by exonucleolytic digestion by the exosome, whereas the 3' fragment is degraded by XRN1. This decay route is shown for several PTC-containing reporters, as well as an endogenous mRNA that is naturally regulated by NMD. We conclude that, despite conservation in the NMD machinery, PTC-containing transcripts are degraded in Drosophila by a mechanism that differs considerably from those described in yeast and mammals(3,6,7).