Abstract
The finding that oxygenase-catalyzed protein hydroxylation regulates animal transcription raises questions as to whether the translation machinery and prokaryotic proteins are analogously modified. Escherichia coli ycfD is a growth-regulating 2-oxoglutarate oxygenase catalyzing arginyl hydroxylation of the ribosomal protein Rpl16. Human ycfD homologs, Myc-induced nuclear antigen (MINA53) and NO66, are also linked to growth and catalyze histidyl hydroxylation of Rpl27a and Rpl8, respectively. This work reveals new therapeutic possibilities via oxygenase inhibition and by targeting modified over unmodified ribosomes.
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Acknowledgements
We thank the Biotechnology and Biological Sciences Research Council (BB/G014124/1 to P.J.R. and C.J.S.), Wellcome Trust (091857/Z/10/Z to P.J.R. and C.J.S.), Cancer Research UK for studentships (to R.S. and A.Z.), the Slovenian Academy of Sciences and Arts (R.S.), the Oxford Cancer Research Centre (M.L.C.) and the Oak Foundation (M.L.C.) for funding. We thank C. Ducho (Georg-August University, Göttingen, Germany) for the kind gift of standards of hydroxyarginine stereoisomers, R. Fischer for generating MS data and U. Ackermann and C. Tessmer for technical assistance in antibody preparation. R.B.H. is on leave from the Department of Pharmacognosy, Assiut University, Egypt.
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W.G., A.W. and T.F. contributed equally; W.G. led in vitro assays and identified substrates by peptide screening, A.W. performed in vivo ycfD experiments and proteomics (with assistance from Z.Z.), and T.F. performed in vivo NO66 experiments. C.-h.H., R.S. and A.Z. contributed equally; C.-h.H. discovered ycfD Arg hydroxylase activity, R.S. analyzed ribosome structures and performed and analyzed all whole protein mass spectrometry, and A.Z. performed in vivo MINA53 experiments. N.G. and M.E.C. performed MINA53 proteomics. R.C. assisted with peptide design. C.L. undertook evolutionary analysis. N.D.L. performed amino acid analyses. T.D.W.C. and R.B.H. undertook NMR. L.G., M.M.M., D.C.T., J.S.M., Y.G., M.Y., P.L.-Y., B.M.K. and C.V.R. performed, supervised or advised on mass analyses. A.Y. designed and supervised shRNA work. A.P.H. and A.T. assisted with MINA53 and ycfD in vitro experiments, respectively. M.S.-Z. developed the NO66 antibody. M.J. synthesized hydroxylated standards. P.J.R. and G.M.P. contributed to the design of the MINA53 and NO66 project and the ycfD project, respectively. M.L.C. and C.J.S. designed and supervised the study, analyzed data and wrote the manuscript with assistance of other authors.
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Ge, W., Wolf, A., Feng, T. et al. Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. Nat Chem Biol 8, 960–962 (2012). https://doi.org/10.1038/nchembio.1093
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DOI: https://doi.org/10.1038/nchembio.1093
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