Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise
Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise
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DOI：
10.1038/ng1429
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发表时间：
2004-10-01
期刊：
影响因子：
30.8
通讯作者：
Dietz, HC
中科院分区：
文献类型：
--
作者：
Mendell, JT;Sharifi, NA;Dietz, HC
过早终止密码子通过无义介导的 mRNA 衰减 (NMD) 诱导真核细胞中转录本快速降解 (1,2)。该途径可以调节无义或移码突变产生的表型，但人们对 NMD 在高等真核生物中的生理作用知之甚少。为了解决这个问题，我们检查了缺乏 Rent1（也称为 hUpf1）的哺乳动物细胞中的表达谱，Rent1 是 NMD3,4 的必需因子。上调的转录物包括在5'非翻译区具有上游开放阅读框的转录物、引入无义密码子或移码的选择性剪接、在3'非翻译区或硒代半胱氨酸密码子中的内含子。来自古代转座子和内源性逆转录病毒的转录本也上调。这些RNA通过在终止密码子下游至少50个核苷酸处存在剪接内含子而统一，该内含子足以启动NMD5。与 NMD 的直接调节一致，在 NMD 缺陷的细胞中，代表性的上调转录本衰减得更慢。此外，氨基酸饥饿诱导的 NMD 抑制会上调促进氨基酸稳态的转录本。这些结果证明无义监视是一种重要的转录后调节事件，影响广泛的生理转录本的表达，已在功能上纳入基本的稳态机制并抑制进化残余物的表达。
Premature termination codons induce rapid transcript degradation in eukaryotic cells through nonsense-mediated mRNA decay (NMD)(1,2). This pathway can modulate phenotypes arising from nonsense or frameshift mutations, but little is known about the physiologic role of NMD in higher eukaryotes. To address this issue, we examined expression profiles in mammalian cells depleted of Rent1 (also called hUpf1), a factor essential for NMD3,4. Upregulated transcripts included those with upstream open reading frames in the 5' untranslated region, alternative splicing that introduces nonsense codons or frameshifts, introns in the 3' untranslated region or selenocysteine codons. Transcripts derived from ancient transposons and endogenous retroviruses were also upregulated. These RNAs are unified by the presence of a spliced intron at least 50 nucleotides downstream of a termination codon, a context sufficient to initiate NMD5. Consistent with direct regulation by NMD, representative upregulated transcripts decayed more slowly in cells deficient in NMD. In addition, inhibition of NMD induced by amino acid starvation upregulated transcripts that promote amino acid homeostasis. These results document that nonsense surveillance is a crucial post-transcriptional regulatory event that influences the expression of broad classes of physiologic transcripts, has been functionally incorporated into essential homeostatic mechanisms and suppresses expression of evolutionary remnants.