Rxivist logo

Tetracyclines Modify Translation By Targeting Key Human rRNA Substructures.

By Jonathan D Mortison, Monica Schenone, Jacob A Myers, Ziyang Zhang, Linfeng Chen, Christie Ciarlo, Eamon Comer, S. Kundhavai Natchiar, Steven A. Carr, Bruno P. Klaholz, Andrew G Myers

Posted 01 Feb 2018
bioRxiv DOI: 10.1101/256230 (published DOI: 10.1016/j.chembiol.2018.09.010)

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.

Download data

  • Downloaded 512 times
  • Download rankings, all-time:
    • Site-wide: 32,479 out of 94,912
    • In cell biology: 1,565 out of 4,894
  • Year to date:
    • Site-wide: 57,303 out of 94,912
  • Since beginning of last month:
    • Site-wide: 78,546 out of 94,912

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)