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 between Gram-negative and Gram-positive organisms have come to light in recent years. Although approximately half of antibiotic-resistant infections are caused by Gram-positive bacteria, major gaps remain in our understanding of how Gram-positives perform ribosome quality control. To address these gaps, my laboratory will focus on two major research areas. 1) We will identify and characterize strategies used by Gram- positive bacteria to detect and rescue stalled ribosomes. Preliminary data from my lab supports a model in which ribosome stalling in B. subtilis and B. anthracis results in frameshifting and premature translation termination. This process is expected to result in toxic truncated proteins and trigger stress responses. We will test this model using biochemical, genetic, and structural approaches. 2) We will determine how ribosome flexibility can be used by the bacterial cell to expand coding capacity. Here, we will investigate how frameshifting and read-through of poorly terminating UAG stop-codons regulates gene expression and identify environmental inputs for this type of regulation. We will use biochemical, structural, and computational approaches to investigate the research themes described above. To further expand this research program, we will use unbiased high throughput genetics to uncover new mechanisms that prevent stalling and that regulate frameshifting and stop codon read- through.