Fail-safe mechanism of GCN4 translational control--uORF2 promotes reinitiation by analogous mechanism to uORF1 and thus secures its key role in GCN4 expression.
Fail-safe mechanism of GCN4 translational control--uORF2 promotes reinitiation by analogous mechanism to uORF1 and thus secures its key role in GCN4 expression.
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DOI：
10.1093/nar/gku204
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发表时间：
2014-05
影响因子：
14.9
通讯作者：
Valášek LS
中科院分区：
文献类型：
--
作者：
Gunišová S;Valášek LS
基因特异性翻译调控的广泛研究机制之一是重新起始。它发生在信使RNA（mRNA）上，其中主ORF之前是上游ORF（uORF）。尽管uORF通常下调主要ORF表达，但存在允许高水平下游ORF表达的特定uORF。关键是他们能够保留40 S亚基的mRNA翻译终止后，恢复扫描下一个八月。在这里，我们利用了典型的模型系统的重新启动，酵母转录激活因子GCN 4的mRNA含有四个短的uORF，并显示，与以前的报告相反，不仅是第一，但其uORF的前两个允许有效的重新启动。引人注目的是，我们证明了它们利用类似的分子机制，依赖于几个顺式作用的5′重启动促进元件，其中一个是它们共享的，以及与翻译起始因子eIF 3的a/TIF 32亚基的相互作用。由于类似的机制也对YAP 1 uORF，我们的研究结果强烈表明，重新启动的基本原则是保守的。此外，存在两个连续的重新起始-允许性uORF，随后是两个重新起始-非允许性uORF，表明GCN 4翻译控制的紧密性由故障安全机制确保，该故障安全机制分别在营养物充足或耗尽条件下有效地防止或触发GCN 4表达。
One of the extensively studied mechanisms of gene-specific translational regulation is reinitiation. It takes place on messenger RNAs (mRNAs) where main ORF is preceded by upstream ORF (uORF). Even though uORFs generally down-regulate main ORF expression, specific uORFs exist that allow high level of downstream ORF expression. The key is their ability to retain 40S subunits on mRNA upon termination of their translation to resume scanning for the next AUG. Here, we took advantage of the exemplary model system of reinitiation, the mRNA of yeast transcriptional activator GCN4 containing four short uORFs, and show that contrary to previous reports, not only the first but the first two of its uORFs allow efficient reinitiation. Strikingly, we demonstrate that they utilize a similar molecular mechanism relying on several cis-acting 5′ reinitiation-promoting elements, one of which they share, and the interaction with the a/TIF32 subunit of translation initiation factor eIF3. Since a similar mechanism operates also on YAP1 uORF, our findings strongly suggest that basic principles of reinitiation are conserved. Furthermore, presence of two consecutive reinitiation-permissive uORFs followed by two reinitiation-non-permissive uORFs suggests that tightness of GCN4 translational control is ensured by a fail-safe mechanism that effectively prevents or triggers GCN4 expression under nutrient replete or deplete conditions, respectively.
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