5' UTR m(6)A Promotes Cap-Independent Translation.
5' UTR m(6)A Promotes Cap-Independent Translation.
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DOI：
10.1016/j.cell.2015.10.012
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发表时间：
2015-11-05
期刊：
影响因子：
64.5
通讯作者：
Jaffrey SR
中科院分区：
文献类型：
--
作者：
Meyer KD;Patil DP;Zhou J;Zinoviev A;Skabkin MA;Elemento O;Pestova TV;Qian SB;Jaffrey SR
蛋白质翻译通常始于43S核糖体复合体被帽结合复合体招募到mRNAs的5‘端。然而，一些文本是通过鲜为人知的机制以不依赖于大小写的方式翻译的。在这里，我们证明了在其5‘非编码区中含有N6-甲基腺苷(M6A)的mRNAs可以以帽不依赖的方式翻译。单个5‘UTRm6A直接与真核细胞启动因子3(EIF3)结合，这足以在没有帽结合因子eIF4E的情况下招募43S复合体启动翻译。抑制腺苷甲基化选择性地减少含有5‘UTRm6A的mRNAs的翻译。此外，Hsp70 mRNA中m6A水平的增加调节其在热休克后的帽子非依赖性翻译。值得注意的是，我们发现不同的细胞应激诱导m6A在转录水平上的重新分布，导致带有5‘UTRm6A的mRNAs数量增加。这些数据表明，5‘UTRm6A绕过了5’帽结合蛋白，促进了胁迫下的翻译。
Protein translation typically begins with the recruitment of the 43S ribosomal complex to the 5′ cap of mRNAs by a cap-binding complex. However, some transcripts are translated in a cap-independent manner through poorly understood mechanisms. Here, we show that mRNAs containing N6-methyladenosine (m6A) in their 5′ UTR can be translated in a cap-independent manner. A single 5′ UTR m6A directly binds eukaryotic initiation factor 3 (eIF3), which is sufficient to recruit the 43S complex to initiate translation in the absence of the cap-binding factor eIF4E. Inhibition of adenosine methylation selectively reduces translation of mRNAs containing 5′UTR m6A. Additionally, increased m6A levels in the Hsp70 mRNA regulate its cap-independent translation following heat shock. Notably, we find that diverse cellular stresses induce a transcriptome-wide redistribution of m6A, resulting in increased numbers of mRNAs with 5′ UTR m6A. These data show that 5′ UTR m6A bypasses 5′ cap-binding proteins to promote translation under stresses.