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首页> 外文期刊>MBio >Translation Initiation from Conserved Non-AUG Codons Provides Additional Layers of Regulation and Coding Capacity
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Translation Initiation from Conserved Non-AUG Codons Provides Additional Layers of Regulation and Coding Capacity

机译：保守的非AUG密码子的翻译起始提供了更多的调节和编码能力

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ABSTRACT Neurospora crassa cpc-1 and Saccharomyces cerevisiae GCN4 are homologs specifying transcription activators that drive the transcriptional response to amino acid limitation. The cpc-1 mRNA contains two upstream open reading frames (uORFs) in its >700-nucleotide?(nt) 5′ leader, and its expression is controlled at the level of translation in response to amino acid starvation. We used N.?crassa cell extracts and obtained data indicating that cpc-1 uORF1 and uORF2 are functionally analogous to GCN4 uORF1 and uORF4, respectively, in controlling translation. We also found that the 5′ region upstream of the main coding sequence of the cpc-1 mRNA extends for more than 700 nucleotides without any in-frame stop codon. For 100 cpc-1 homologs from Pezizomycotina and from selected Basidiomycota, 5′ conserved extensions of the CPC1 reading frame are also observed. Multiple non-AUG near-cognate codons (NCCs) in the CPC1 reading frame upstream of uORF2, some deeply conserved, could potentially initiate translation. At least four NCCs initiated translation in vitro . In vivo data were consistent with initiation at NCCs to produce N-terminally extended N.?crassa CPC1 isoforms. The pivotal role played by CPC1, combined with its translational regulation by uORFs and NCC utilization, underscores the emerging significance of noncanonical initiation events in controlling gene expression. IMPORTANCE There is a deepening and widening appreciation of the diverse roles of translation in controlling gene expression. A central fungal transcription factor, the best-studied example of which is Saccharomyces cerevisiae GCN4, is crucial for the response to amino acid limitation. Two upstream open reading frames (uORFs) in the GCN4 mRNA are critical for controlling GCN4 synthesis. We observed that two uORFs in the corresponding Neurospora crassa cpc-1 mRNA appear functionally analogous to the GCN4 uORFs. We also discovered that, surprisingly, unlike GCN4, the CPC1 coding sequence extends far upstream from the presumed AUG start codon with no other in-frame AUG codons. Similar extensions were seen in homologs from many filamentous fungi. We observed that multiple non-AUG near-cognate codons (NCCs) in this extended reading frame, some conserved, initiated translation to produce longer forms of CPC1, underscoring the significance of noncanonical initiation in controlling gene expression.
机译：摘要Neurospora crassa cpc-1和Saccharomyces cerevisiae GCN4是指定转录激活因子的同源物，该激活因子驱动对氨基酸限制的转录反应。 cpc-1 mRNA在> 700核苷酸？（nt）5'前导序列中包含两个上游开放阅读框（uORF），其表达被控制在响应氨基酸饥饿的翻译水平。我们使用了N.crassa细胞提取物，获得的数据表明cpc-1 uORF1和uORF2在控制翻译中分别在功能上类似于GCN4 uORF1和uORF4。我们还发现，cpc-1 mRNA主要编码序列上游的5'区延伸了700多个核苷酸，而没有任何符合读框的终止密码子。对于来自Pezizomycotina和选定的Basidiomycota的100 cpc-1同源物，还观察到了CPC1阅读框的5'保守延伸。 uORF2上游CPC1读框中的多个非AUG近同源密码子（NCC），有一些是非常保守的，可能潜在地启动翻译。至少有4个NCC启动了体外翻译。体内数据与在NCC产生N末端延伸的N.crassa CPC1亚型的起始一致。 CPC1发挥的关键作用，再加上uORF和NCC利用的翻译调控作用，突显了非规范启动事件在控制基因表达中的新兴重要性。重要性对翻译在控制基因表达中的各种作用的认识正在加深和扩大。一个中央真菌转录因子，其研究最多的例子是酿酒酵母GCN4，对氨基酸限制的反应至关重要。 GCN4 mRNA中的两个上游开放阅读框（uORF）对于控制GCN4合成至关重要。我们观察到在相应的神经孢霉cpc-1 mRNA中的两个uORF似乎在功能上类似于GCN4 uORF。我们还惊奇地发现，与GCN4不同，CPC1编码序列从假定的AUG起始密码子向上游延伸得很远，而没有其他帧内AUG密码子。在来自许多丝状真菌的同源物中也观察到类似的延伸。我们观察到在此扩展阅读框中的多个非AUG近同源密码子（NCC），有些保守且启动了翻译以产生更长的形式的CPC1，从而强调了非规范启动在控制基因表达中的重要性。

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