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Chemical modulators of ribosome biogenesis as biological probes

Nature Chemical Biology volume 11, pages 924–932 (2015)Cite this article

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Abstract

Small-molecule inhibitors of protein biosynthesis have been instrumental in the dissection of the complexities of ribosome structure and function. Ribosome biogenesis, on the other hand, is a complex and largely enigmatic process for which there is a paucity of chemical probes. Indeed, ribosome biogenesis has been studied almost exclusively using genetic and biochemical approaches without the benefit of small-molecule inhibitors of this process. Here, we provide a perspective on the promise of chemical inhibitors of ribosome assembly for future research. We explore key obstacles that complicate the interpretation of studies aimed at perturbing ribosome biogenesis in vivo using genetic methods, and we argue that chemical inhibitors are especially powerful because they can be used to induce perturbations in a manner that obviates these difficulties. Thus, in combination with leading-edge biochemical and structural methods, chemical probes offer unique advantages toward elucidating the molecular events that define the assembly of ribosomes.

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Figure 1: Simplified overview of ribosome biogenesis.
Figure 2: Classical methods to study ribosome biogenesis in E. coli.
Figure 3: Genetic perturbation of ribosome biogenesis factors lacks temporal resolution and can lead to multiple unrelated phenotypic effects.
Figure 4: Small-molecule inhibitors of ribosome biogenesis provide kinetic resolution of events following perturbation.

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Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery Grant to E.D.B.), by a salary award to E.D.B. from the Canada Research Chairs program, and by scholarships awarded to J.M.S. from the Canadian Institutes of Health Research and the Ontario Graduate Scholarships program.

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  1. Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada

    Jonathan M Stokes & Eric D Brown

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Stokes, J., Brown, E. Chemical modulators of ribosome biogenesis as biological probes. Nat Chem Biol 11, 924–932 (2015). https://doi.org/10.1038/nchembio.1957

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