Department of Biological Engineering
Massachusetts Institute of Technology
Singapore-MIT Alliance for Research and Technology
Infectious Disease IRG, Singapore
Host: John Hunt
Title: A system of tRNA modifications and an alternative genetic code control the mycobacterial stress response and antibiotic resistance
Abstract: Systems-level technologies such as genomics and RNA-seq have provided critical insights into transcription as a determinant of gene expression. Translation, on the other hand, presents structural and operational complexities that have confounded our understanding of this major link between genotype and phenotype. Among the most poorly understood components of the translational machinery are the dozens of modified ribonucleosides in tRNA and rRNA. Using a variety of systems-level ‘omic technologies, we have identified coordination between stress-specific reprogramming of tRNA modifications and the selective translation of proteins from families of stress-response genes with matching codon usage biases. Here we illustrate this behavior in the response of pathogenic mycobacteria to the stresses of hypoxia and nutrient deprivation characteristic of tuberculous granulomas. Focusing on Mycobacterium bovis BCG, an M. tuberculosis surrogate, we observed signature reprogramming of 40 tRNA modifications at each stage of hypoxic dormancy and aerobic resuscitation, with this reprogramming linked to selective translation of transcripts from families of codon-biased genes, such as the DosR master regulator of hypoxic dormancy. A different pattern of tRNA reprogramming occurs in response to nutrient deprivation, with the i6A modification at position 37 in tRNA playing a critical role in the antibiotic tolerance of the mycobacterial dormant state. Ongoing studies illustrate the generality of this mechanism in human cancer, the life cycle of malaria parasites, and dengue virus infection.