Ribosome Quality Control Mechanisms in Gram-positive Bacteria

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Project Summary: Although bacterial ribosomes have been biochemically interrogated for decades, unknown mechanisms of regulation and quality control are regularly uncovered and targeted with new antibiotics. Major differences in translation regulation between Gram-positive and Gram-negative bacteria have come to light in recent years. Although more than 200,000 infections per year in the United States are caused by antibiotic resistant Gram- positive bacteria, major gaps remain in our understanding of how Gram-positives perform ribosome quality control. To address these gaps, my research program will focus on two major areas. 1) We will identify and characterize strategies used by Gram-positive bacteria to detect and rescue stalled ribosomes and investigate the physiological impacts of ribosome stalling. Preliminary data from my laboratory supports a model in which ribosome stalling in Bacillus subtilis and Bacillus anthracis results in frameshifting and premature translation termination. This process is expected to result in toxic truncated proteins and trigger stress responses. We will investigate this model using genetic, structural, and biochemical approaches. 2) We will determine how ribosome flexibility and atypical translation events can be used by the cell to increase coding capacity. We are particularly interested in how frameshifting and stop codon read-through regulates gene expression and how environmental inputs control this type of regulation. We will also use unbiased high throughput genetics to uncover new mechanisms that prevent stalling and that regulate programmed frameshifting and stop codon read-through.