MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Center for Synthetic & Systems Biology, Tsinghua University, Beijing, 100084, China.
Nat Commun. 2023 Feb 2;14(1):553. doi: 10.1038/s41467-023-36290-w.
The quickly accumulating ribosome profiling data is an insightful resource for studying the critical details of translation regulation under various biological contexts. Rocaglamide A (RocA), an antitumor heterotricyclic natural compound, has been shown to inhibit translation initiation of a large group of mRNA species by clamping eIF4A onto poly-purine motifs in the 5' UTRs. However, reanalysis of previous ribosome profiling datasets reveals an unexpected shift of the ribosome occupancy pattern, upon RocA treatment in various types of cells, during early translation elongation for a specific group of mRNA transcripts without poly-purine motifs over-represented in their 5' UTRs. Such perturbation of translation elongation dynamics can be attributed to the blockage of translating ribosomes due to the binding of eIF4A to the poly-purine sequence in coding regions. In summary, our study presents the complete dual modes of RocA in blocking translation initiation and elongation, which underlie the potent antitumor effect of RocA.
核糖体图谱数据的快速积累为研究各种生物背景下翻译调控的关键细节提供了有价值的资源。罗卡酰胺 A（RocA）是一种抗肿瘤杂环天然化合物，它通过将 eIF4A 夹在 5'UTR 中的多嘌呤基序上，来抑制一大类 mRNA 物种的翻译起始。然而，对以前核糖体图谱数据集的重新分析显示，在各种类型的细胞中，罗卡酰胺处理后，在早期翻译延伸过程中，一组特定的 mRNA 转录本的核糖体占据模式发生了意外的变化，这些转录本的 5'UTR 中并没有过度表达多嘌呤基序。这种翻译延伸动力学的扰动可以归因于翻译核糖体的阻断，因为 eIF4A 与编码区域中的多嘌呤序列结合。总之，我们的研究揭示了罗卡酰胺在阻断翻译起始和延伸中的两种完全模式，这是罗卡酰胺抗肿瘤作用的基础。
