The protein kinase Gcn2 is a central transducer of nutritional stress signaling important for stress adaptation by normal cells and the survival of cancer cells. In response to nutrient deprivation, Gcn2 phosphorylates eIF2α, thereby repressing general translation while enhancing translation of specific mRNAs with upstream ORFs (uORFs) situated in their 5′-leader regions. Here we performed genome-wide measurements of mRNA translation during histidine starvation in fission yeast Schizosaccharomyces pombe. Polysome analyses were combined with microarray measurements to identify gene transcripts whose translation was up-regulated in response to the stress in a Gcn2-dependent manner. We determined that translation is reprogrammed to enhance RNA metabolism and chromatin regulation and repress ribosome synthesis. Interestingly, translation of intron-containing mRNAs was up-regulated. The products of the regulated genes include additional eIF2α kinase Hri2 amplifying the stress signaling and Gcn5 histone acetyl transferase and transcription factors, together altering genome-wide transcription. Unique dipeptide-coding uORFs and nucleotide motifs, such as ‘5′-UGA(C/G)GG-3′, are found in 5′ leader regions of regulated genes and shown to be responsible for translational control.

中文翻译：

---

Gcn2 eIF2α 激酶通过靶 mRNA 中的核苷酸基序和 uORF 介导组合翻译调节。


蛋白激酶 Gcn2 是营养应激信号传导的中心转导器，对于正常细胞的应激适应和癌细胞的生存至关重要。为了应对营养缺乏，Gcn2 磷酸化 eIF2α，从而抑制一般翻译，同时增强上游 ORF (uORF) 位于其 5'-前导区域的特定 mRNA 的翻译。在这里，我们对裂殖酵母裂殖酵母组氨酸饥饿期间的 mRNA 翻译进行了全基因组测量。多核糖体分析与微阵列测量相结合，以鉴定其翻译以 Gcn2 依赖性方式响应应激而上调的基因转录本。我们确定翻译被重新编程以增强 RNA 代谢和染色质调节并抑制核糖体合成。有趣的是，含有内含子的 mRNA 的翻译被上调。受调节基因的产物包括额外的 eIF2α 激酶 Hri2（放大应激信号）和 Gcn5 组蛋白乙酰转移酶和转录因子，共同改变全基因组转录。独特的二肽编码 uORF 和核苷酸基序，例如“5'-UGA(C/G)GG-3'”，存在于受调节基因的 5' 前导区域中，并被证明负责翻译控制。