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Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-10-11 , DOI: 10.1016/j.chembiol.2018.09.010 Jonathan D Mortison 1 , Monica Schenone 2 , Jacob A Myers 1 , Ziyang Zhang 1 , Linfeng Chen 1 , Christie Ciarlo 2 , Eamon Comer 2 , S Kundhavai Natchiar 3 , Steven A Carr 2 , Bruno P Klaholz 3 , Andrew G Myers 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-10-11 , DOI: 10.1016/j.chembiol.2018.09.010 Jonathan D Mortison 1 , Monica Schenone 2 , Jacob A Myers 1 , Ziyang Zhang 1 , Linfeng Chen 1 , Christie Ciarlo 2 , Eamon Comer 2 , S Kundhavai Natchiar 3 , Steven A Carr 2 , Bruno P Klaholz 3 , Andrew G Myers 1
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Apart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in-cell click selective crosslinking with RNA sequence profiling (icCL-seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution. Importantly, we found that structurally and phenotypically variant tetracycline analogs could chemically discriminate these rRNA binding sites. We also found that tetracyclines both subtly modify human ribosomal translation and selectively activate the cellular integrated stress response (ISR). Together, the data reveal that targeting of specific rRNA substructures, activation of the ISR, and inhibition of translation are correlated with the anti-proliferative properties of tetracyclines in human cancer cell lines.
中文翻译：
四环素通过靶向关键的人类rRNA亚结构来修饰翻译。
除了其抗菌特性外，四环素还具有改善病理性炎症和人类癌症的经临床验证的作用。然而，对造成这些影响的目标和机制的描述仍然难以捉摸。在这里，采用基于定量质谱的蛋白质组学，我们确定了人类80S核糖体为四环素Col-3和强力霉素的靶标。然后，我们开发了利用RNA序列分析（icCL-seq）进行的细胞内点击选择性交联，以核苷酸分辨率解析这些四环素在关键人rRNA亚结构上的结合位点。重要的是，我们发现结构和表型上的四环素类似物变体可以化学区分这些rRNA结合位点。我们还发现四环素既可以巧妙地修饰人核糖体翻译，又可以选择性激活细胞整合应激反应（ISR）。总之，数据揭示了针对特定rRNA亚结构的靶向，ISR的激活和翻译的抑制与四环素在人类癌细胞系中的抗增殖特性有关。
更新日期：2018-10-12
中文翻译：
四环素通过靶向关键的人类rRNA亚结构来修饰翻译。
除了其抗菌特性外，四环素还具有改善病理性炎症和人类癌症的经临床验证的作用。然而，对造成这些影响的目标和机制的描述仍然难以捉摸。在这里，采用基于定量质谱的蛋白质组学，我们确定了人类80S核糖体为四环素Col-3和强力霉素的靶标。然后，我们开发了利用RNA序列分析（icCL-seq）进行的细胞内点击选择性交联，以核苷酸分辨率解析这些四环素在关键人rRNA亚结构上的结合位点。重要的是，我们发现结构和表型上的四环素类似物变体可以化学区分这些rRNA结合位点。我们还发现四环素既可以巧妙地修饰人核糖体翻译，又可以选择性激活细胞整合应激反应（ISR）。总之，数据揭示了针对特定rRNA亚结构的靶向，ISR的激活和翻译的抑制与四环素在人类癌细胞系中的抗增殖特性有关。
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