Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cell Chemical Biology Year : 2018

Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures


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.
Embargoed file
Embargoed file
Ne sera jamais visible

Dates and versions

inserm-02409770 , version 1 (13-12-2019)



Jonathan Mortison, Monica Schenone, Jacob Myers, Ziyang Zhang, Linfeng Chen, et al.. Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures. Cell Chemical Biology, 2018, 25 (12), pp.1506-1518.e13. ⟨10.1016/j.chembiol.2018.09.010⟩. ⟨inserm-02409770⟩
70 View
2 Download



Gmail Facebook X LinkedIn More