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tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence

Yok Hian Chionh, Megan McBee, I. Ramesh Babu, Fabian Hia, Wenwei Lin, Wei Zhao, Jianshu Cao, Agnieszka Dziergowska, Andrzej Malkiewicz, Thomas J. Begley, Sylvie Alonso and Peter C. Dedon ()
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Yok Hian Chionh: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
Megan McBee: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
I. Ramesh Babu: Massachusetts Institute of Technology
Fabian Hia: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
Wenwei Lin: Yong Loo Lin School of Medicine, 28 Medical Drive, Centre for Life Sciences, Level 3, National University of Singapore
Wei Zhao: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
Jianshu Cao: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
Agnieszka Dziergowska: Institute of Organic Chemistry, Lodz University of Technology
Andrzej Malkiewicz: Institute of Organic Chemistry, Lodz University of Technology
Thomas J. Begley: College of Nanoscale Science and Engineering, State University of New York
Sylvie Alonso: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology
Peter C. Dedon: Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria—which models tuberculous granulomas—are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes. For example, early hypoxia increases wobble cmo5U in tRNAThr(UGU), which parallels translation of transcripts enriched in its cognate codon, ACG, including the DosR master regulator of hypoxic bacteriostasis. Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria.

Date: 2016
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DOI: 10.1038/ncomms13302

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