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Chemical modulators of ribosome biogenesis as biological probes

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.

References

  1. Ban, N., Nissen, P., Hansen, J., Moore, P.B. & Steitz, T.A. The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. Science 289, 905–920 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Wimberly, B.T. et al. Structure of the 30S ribosomal subunit. Nature 407, 327–339 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Yusupov, M.M. et al. Crystal structure of the ribosome at 5.5 A resolution. Science 292, 883–896 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Shajani, Z., Sykes, M.T. & Williamson, J.R. Assembly of bacterial ribosomes. Annu. Rev. Biochem. 80, 501–526 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Holmes, K.L. & Culver, G.M. Analysis of conformational changes in 16S rRNA during the course of 30S subunit assembly. J. Mol. Biol. 354, 340–357 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Williamson, J.R. Assembly of the 30S ribosomal subunit. Q. Rev. Biophys. 38, 397–403 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Kim, H. et al. Protein-guided RNA dynamics during early ribosome assembly. Nature 506, 334–338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bunner, A.E., Beck, A.H. & Williamson, J.R. Kinetic cooperativity in Escherichia coli 30S ribosomal subunit reconstitution reveals additional complexity in the assembly landscape. Proc. Natl. Acad. Sci. USA 107, 5417–5422 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Johnson, A.W., Lund, E. & Dahlberg, J. Nuclear export of ribosomal subunits. Trends Biochem. Sci. 27, 580–585 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Strunk, B.S. et al. Ribosome assembly factors prevent premature translation initiation by 40S assembly intermediates. Science 333, 1449–1453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Strunk, B.S., Novak, M.N., Young, C.L. & Karbstein, K. A translation-like cycle is a quality control checkpoint for maturing 40S ribosome subunits. Cell 150, 111–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lindahl, L. Intermediates and time kinetics of the in vivo assembly of Escherichia coli ribosomes. J. Mol. Biol. 92, 15–37 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Lindahl, L. Two new ribosomal precursor particles in E. coli. Nat. New Biol. 243, 170–172 (1973).

    Article  CAS  PubMed  Google Scholar 

  14. Sykes, M.T., Shajani, Z., Sperling, E., Beck, A.H. & Williamson, J.R. Quantitative proteomic analysis of ribosome assembly and turnover in vivo. J. Mol. Biol. 403, 331–345 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lerner, C.G. & Inouye, M. Pleiotropic changes resulting from depletion of Era, an essential GTP-binding protein in Escherichia coli. Mol. Microbiol. 5, 951–957 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Armistead, J. & Triggs-Raine, B. Diverse diseases from a ubiquitous process: the ribosomopathy paradox. FEBS Lett. 588, 1491–1500 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Falconer, S.B., Czarny, T.L. & Brown, E.D. Antibiotics as probes of biological complexity. Nat. Chem. Biol. 7, 415–423 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Wilson, D.N. The A-Z of bacterial translation inhibitors. Crit. Rev. Biochem. Mol. Biol. 44, 393–433 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Wilson, D.N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat. Rev. Microbiol. 12, 35–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Tissières, A. & Watson, J.D. Ribonucleoprotein particles from Escherichia coli. Nature 182, 778–780 (1958).

    Article  PubMed  Google Scholar 

  21. Hosokawa, K., Fujimura, R.K. & Nomura, M. Reconstitution of functionally active ribosomes from inactive subparticles and proteins. Proc. Natl. Acad. Sci. USA 55, 198–204 (1966).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Traub, P. & Nomura, M. Structure and function of Escherichia coli ribosomes. J. Mol. Biol. 40, 391–413 (1969).

    Article  CAS  PubMed  Google Scholar 

  23. Mizushima, S. & Nomura, M. Assembly mapping of 30S ribosomal proteins from E. coli. Nature 226, 1214–1218 (1970).

    Article  CAS  PubMed  Google Scholar 

  24. Nierhaus, K.H. & Dohme, F. Total reconstitution of functionally active 50S ribosomal subunits from Escherichia coli. Proc. Natl. Acad. Sci. USA 71, 4713–4717 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Röhl, R. & Nierhaus, K.H. Assembly map of the large subunit (50S) of Escherichia coli ribosomes. Proc. Natl. Acad. Sci. USA 79, 729–733 (1982).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Adilakshmi, T., Bellur, D.L. & Woodson, S.A. Concurrent nucleation of 16S folding and induced fit in 30S ribosome assembly. Nature 455, 1268–1272 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bunner, A.E., Trauger, S.A., Siuzdak, G. & Williamson, J.R. Quantitative ESI-TOF analysis of macromolecular assembly kinetics. Anal. Chem. 80, 9379–9386 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mulder, A.M. et al. Visualizing ribosome biogenesis: parallel assembly pathways for the 30S subunit. Science 330, 673–677 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tai, P.C., Kessler, D.P. & Ingraham, J. Cold-sensitive mutations in Salmonella typhimurium which affect ribosome synthesis. J. Bacteriol. 97, 1298–1304 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. MacDonald, R.E., Turnock, G. & Forchhammer, J. The synthesis and function of ribosomes in a new mutant of Escherichia coli. Proc. Natl. Acad. Sci. USA 57, 141–147 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nikolaev, N., Silengo, L. & Schlessinger, D. A role for ribonuclease III in processing of ribosomal ribonucleic acid and messenger ribonucleic acid precursors in Escherichia coli. J. Biol. Chem. 248, 7967–7969 (1973).

    CAS  PubMed  Google Scholar 

  32. Ginsburg, D. & Steitz, J.A. The 30 S ribosomal precursor RNA from Escherichia coli. A primary transcript containing 23 S, 16 S, and 5 S sequences. J. Biol. Chem. 250, 5647–5654 (1975).

    CAS  PubMed  Google Scholar 

  33. Sirdeshmukh, R. & Schlessinger, D. Ordered processing of Escherichia coli 23S rRNA in vitro. Nucleic Acids Res. 13, 5041–5054 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ghora, B.K. & Apirion, D. Identification of a novel RNA molecule in a new RNA processing mutant of Escherichia coli which contains 5 S rRNA sequences. J. Biol. Chem. 254, 1951–1956 (1979).

    CAS  PubMed  Google Scholar 

  35. Li, Z., Pandit, S. & Deutscher, M.P. RNase G (CafA protein) and RNase E are both required for the 5′ maturation of 16S ribosomal RNA. EMBO J. 18, 2878–2885 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bakin, A. & Ofengand, J. Four newly located pseudouridylate residues in Escherichia coli 23S ribosomal RNA are all at the peptidyltransferase center: analysis by the application of a new sequencing technique. Biochemistry 32, 9754–9762 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Green, R. & Noller, H.F. In vitro complementation analysis localizes 23S rRNA posttranscriptional modifications that are required for Escherichia coli 50S ribosomal subunit assembly and function. RNA 2, 1011–1021 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Decatur, W.A. & Fournier, M.J. rRNA modifications and ribosome function. Trends Biochem. Sci. 27, 344–351 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Cumberlidge, A.G. & Isono, K. Ribosomal protein modification in Escherichia coli. I. A mutant lacking the N-terminal acetylation of protein S5 exhibits thermosensitivity. J. Mol. Biol. 131, 169–189 (1979).

    Article  CAS  PubMed  Google Scholar 

  40. Kushner, S.R., Maples, V.F. & Champney, W.S. Conditionally lethal ribosomal protein mutants: characterization of a locus required for modification of 50S subunit proteins. Proc. Natl. Acad. Sci. USA 74, 467–471 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nierhaus, K.H. The assembly of prokaryotic ribosomes. Biochimie 73, 739–755 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Nishi, K., Morel-Deville, F., Hershey, J.W., Leighton, T. & Schnier, J. An eIF-4A-like protein is a suppressor of an Escherichia coli mutant defective in 50S ribosomal subunit assembly. Nature 336, 496–498 (1988).

    Article  CAS  PubMed  Google Scholar 

  43. Dammel, C.S. & Noller, H.F. Suppression of a cold-sensitive mutation in 16S rRNA by overexpression of a novel ribosome-binding factor, RbfA. Genes Dev. 9, 626–637 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Karbstein, K. Role of GTPases in ribosome assembly. Biopolymers 87, 1–11 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Britton, R.A. Role of GTPases in bacterial ribosome assembly. Annu. Rev. Microbiol. 63, 155–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Woolford, J.L. & Baserga, S.J. Ribosome biogenesis in the yeast Saccharomyces cerevisiae. Genetics 195, 643–681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kaczanowska, M. & Rydén-Aulin, M. Ribosome biogenesis and the translation process in Escherichia coli. Microbiol. Mol. Biol. Rev. 71, 477–494 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maguire, B.A. Inhibition of bacterial ribosome assembly: a suitable drug target? Microbiol. Mol. Biol. Rev. 73, 22–35 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gollop, N. & March, P.E. A GTP-binding protein (Era) has an essential role in growth rate and cell cycle control in Escherichia coli. J. Bacteriol. 173, 2265–2270 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Britton, R.A. et al. Cell cycle arrest in Era GTPase mutants: a potential growth rate-regulated checkpoint in Escherichia coli. Mol. Microbiol. 27, 739–750 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Sayed, A., Matsuyama, S.I. & Inouye, M. Era, an essential Escherichia coli small G-protein, binds to the 30S ribosomal subunit. Biochem. Biophys. Res. Commun. 264, 51–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Inoue, K., Alsina, J., Chen, J. & Inouye, M. Suppression of defective ribosome assembly in a rbfA deletion mutant by overexpression of Era, an essential GTPase in Escherichia coli. Mol. Microbiol. 48, 1005–1016 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Sharma, M.R. et al. Interaction of Era with the 30S ribosomal subunit implications for 30S subunit assembly. Mol. Cell 18, 319–329 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Stokes, J.M., Davis, J.H., Mangat, C.S., Williamson, J.R. & Brown, E.D. Discovery of a small molecule that inhibits bacterial ribosome biogenesis. Elife 3, e03574 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Campbell, T.L. & Brown, E.D. Genetic interaction screens with ordered overexpression and deletion clone sets implicate the Escherichia coli GTPase YjeQ in late ribosome biogenesis. J. Bacteriol. 190, 2537–2545 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jomaa, A. et al. Cryo-electron microscopy structure of the 30S subunit in complex with the YjeQ biogenesis factor. RNA 17, 2026–2038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Himeno, H. et al. A novel GTPase activated by the small subunit of ribosome. Nucleic Acids Res. 32, 5303–5309 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Siibak, T. et al. Erythromycin- and chloramphenicol-induced ribosomal assembly defects are secondary effects of protein synthesis inhibition. Antimicrob. Agents Chemother. 53, 563–571 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Usary, J. & Champney, W.S. Erythromycin inhibition of 50S ribosomal subunit formation in Escherichia coli cells. Mol. Microbiol. 40, 951–962 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Siibak, T. et al. Antibiotic-induced ribosomal assembly defects result from changes in the synthesis of ribosomal proteins. Mol. Microbiol. 80, 54–67 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Champney, W.S. & Burdine, R. 50S ribosomal subunit synthesis and translation are equivalent targets for erythromycin inhibition in Staphylococcus aureus. Antimicrob. Agents Chemother. 40, 1301–1303 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Champney, W.S. & Burdine, R. Azithromycin and clarithromycin inhibition of 50S ribosomal subunit formation in Staphylococcus aureus cells. Curr. Microbiol. 36, 119–123 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Champney, W.S. & Tober, C.L. Evernimicin (SCH27899) inhibits both translation and 50S ribosomal subunit formation in Staphylococcus aureus cells. Antimicrob. Agents Chemother. 44, 1413–1417 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McGaha, S.M. & Champney, W.S. Hygromycin B inhibition of protein synthesis and ribosome biogenesis in Escherichia coli. Antimicrob. Agents Chemother. 51, 591–596 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Champney, W.S. The other target for ribosomal antibiotics: inhibition of bacterial ribosomal subunit formation. Infect. Disord. Drug Targets 6, 377–390 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Bremer, H. & Dennis, P.P. Modulation of chemical composition and other parameters of the cell by growth rate. In: Escherichia coli and Salmonella: Cellular and Molecular Biology 2nd edn. (ASM Press, Washington, DC, 1996).

  67. Chen, S.S. & Williamson, J.R. Characterization of the ribosome biogenesis landscape in E. coli using quantitative mass spectrometry. J. Mol. Biol. 425, 767–779 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Chen, S.S., Sperling, E., Silverman, J.M., Davis, J.H. & Williamson, J.R. Measuring the dynamics of E. coli ribosome biogenesis using pulse-labeling and quantitative mass spectrometry. Mol. Biosyst. 8, 3325–3334 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Charollais, J., Dreyfus, M. & Iost, I. CsdA, a cold-shock RNA helicase from Escherichia coli, is involved in the biogenesis of 50S ribosomal subunit. Nucleic Acids Res. 32, 2751–2759 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moreno, J.M., Drskjøtersen, L., Kristensen, J.E., Mortensen, K.K. & Sperling-Petersen, H.U. Characterization of the domains of E. coli initiation factor IF2 responsible for recognition of the ribosome. FEBS Lett. 455, 130–134 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Arrowsmith, C.H. et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Loibl, M. et al. The drug diazaborine blocks ribosome biogenesis by inhibiting the AAA-ATPase Drg1. J. Biol. Chem. 289, 3913–3922 (2014).

    Article  PubMed  Google Scholar 

  73. Pertschy, B. et al. Diazaborine treatment of yeast cells inhibits maturation of the 60S ribosomal subunit. Mol. Cell. Biol. 24, 6476–6487 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pertschy, B. et al. Cytoplasmic recycling of 60S preribosomal factors depends on the AAA protein Drg1. Mol. Cell. Biol. 27, 6581–6592 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kappel, L. et al. Rlp24 activates the AAA-ATPase Drg1 to initiate cytoplasmic pre-60S maturation. J. Cell Biol. 199, 771–782 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Saveanu, C. et al. Sequential protein association with nascent 60S ribosomal particles. Mol. Cell. Biol. 23, 4449–4460 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Drygin, D. et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 71, 1418–1430 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Bywater, M.J. et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51–65 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Deisenroth, C. & Zhang, Y. Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway. Oncogene 29, 4253–4260 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Drygin, D. et al. Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res. 69, 7653–7661 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Lewis, K. Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Frazier, A.D. & Champney, W.S. The vanadyl ribonucleoside complex inhibits ribosomal subunit formation in Staphylococcus aureus. J. Antimicrob. Chemother. 67, 2152–2157 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Frazier, A.D. & Champney, W.S. Inhibition of ribosomal subunit synthesis in Escherichia coli by the vanadyl ribonucleoside complex. Curr. Microbiol. 67, 226–233 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Silvers, J.A. & Champney, W.S. Accumulation and turnover of 23S ribosomal RNA in azithromycin-inhibited ribonuclease mutant strains of Escherichia coli. Arch. Microbiol. 184, 66–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Rasmussen, L.C., Sperling-Petersen, H.U. & Mortensen, K.K. Hitting bacteria at the heart of the central dogma: sequence-specific inhibition. Microb. Cell Fact. 6, 24 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Xue-Wen, H., Jie, P., Xian-Yuan, A. & Hong-Xiang, Z. Inhibition of bacterial translation and growth by peptide nucleic acids targeted to domain II of 23S rRNA. J. Pept. Sci. 13, 220–226 (2007).

    Article  PubMed  CAS  Google Scholar 

  87. Klostermeier, D., Sears, P., Wong, C.H., Millar, D.P. & Williamson, J.R. A three-fluorophore FRET assay for high-throughput screening of small-molecule inhibitors of ribosome assembly. Nucleic Acids Res. 32, 2707–2715 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bharat, A., Blanchard, J.E. & Brown, E.D. A high-throughput screen of the GTPase activity of Escherichia coli EngA to find an inhibitor of bacterial ribosome biogenesis. J. Biomol. Screen. 18, 830–836 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Bharat, A. & Brown, E.D. Phenotypic investigations of the depletion of EngA in Escherichia coli are consistent with a role in ribosome biogenesis. FEMS Microbiol. Lett. 353, 26–32 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Gadal, O. et al. Rlp7p is associated with 60S preribosomes, restricted to the granular component of the nucleolus, and required for pre-rRNA processing. J. Cell Biol. 157, 941–951 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Grandi, P. et al. 90S pre-ribosomes include the 35S pre-rRNA, the U3 snoRNP, and 40S subunit processing factors but predominantly lack 60S synthesis factors. Mol. Cell 10, 105–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Karbstein, K. Quality control mechanisms during ribosome maturation. Trends Cell Biol. 23, 242–250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cheng, Z.F. & Deutscher, M.P. Quality control of ribosomal RNA mediated by polynucleotide phosphorylase and RNase R. Proc. Natl. Acad. Sci. USA 100, 6388–6393 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Jacob, A.I., Köhrer, C., Davies, B.W., Rajbhandary, U.L. & Walker, G.C. Conserved bacterial RNase YbeY plays key roles in 70S ribosome quality control and 16S rRNA maturation. Mol. Cell 49, 427–438 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Cole, S.E., LaRiviere, F.J., Merrikh, C.N. & Moore, M.J. A convergence of rRNA and mRNA quality control pathways revealed by mechanistic analysis of nonfunctional rRNA decay. Mol. Cell 34, 440–450 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Davies, B.W. et al. Role of Escherichia coli YbeY, a highly conserved protein, in rRNA processing. Mol. Microbiol. 78, 506–518 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Golovina, A.Y., Bogdanov, A.A., Dontsova, O.A. & Sergiev, P.V. Purification of 30S ribosomal subunit by streptavidin affinity chromatography. Biochimie 92, 914–917 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Leonov, A.A., Sergiev, P.V., Bogdanov, A.A., Brimacombe, R. & Dontsova, O.A. Affinity purification of ribosomes with a lethal G2655C mutation in 23 S rRNA that affects the translocation. J. Biol. Chem. 278, 25664–25670 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Bassler, J. et al. Identification of a 60S preribosomal particle that is closely linked to nuclear export. Mol. Cell 8, 517–529 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Stokes, J.M., Selin, C., Cardona, S.T. & Brown, E.D. Chemical inhibition of bacterial ribosome biogenesis shows efficacy in a worm infection model. Antimicrob. Agents Chemother. 59, 2918–2920 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ghalei, H. et al. Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth. J. Cell Biol. 208, 745–759 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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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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