Description
Mortison JD, Schenone M, Myers JA, Zhang Z, Chen L, Ciarlo C, Comer E, Natchiar SK, Carr SA, Klaholz BP, Myers AG. Cell Chem Bio 2018. 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.
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: SILAC
Contact
Principal Investigators:
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Steven A. Carr, Broad Institute of MIT and Harvard, United States
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clauser
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Distinct condition labels are counted across all files submitted in the "Metadata" category
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Originally identified proteins that were automatically
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Number of distinct peptide sequences (including modified variants or peptidoforms) reported
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Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
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A protein is differentially abundant if its change in abundance across conditions is found
to be statistically significant with an adjusted p-value <= 0.05 and lists no issues associated
with statistical tests for differential abundance.
Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
of Quantified Analytes" category having a "Protein" column in this dataset.
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This dataset may not contain all raw spectra data as originally deposited in PRIDE.
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