Physical Mechanisms of Bacterial Genome Maintenance

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DESCRIPTION (provided by applicant): Bacterial single-strand (ss) DNA-binding proteins (SSBs) play essential protective and organizational roles in genome biology. To shield ssDNA from potential damage, multiple SSBs assemble into "nucleosome-like" scaffolds, the structures of which are not well understood. Far from being inert, ssDNA/SSB complexes are active DNA processing centers where at least a dozen different enzymes gain access to genomic substrates by exploiting direct protein-protein interactions with SSB. In all cases examined to date, SSB's flexible C-terminus (SSB-Ct) forms a docking site for heterologous proteins. How proteins bind to the SSB-Ct sequence and how these essential interactions affect the activities of genome maintenance enzymes remains poorly defined. Given the importance of SSB's interactions with heterologous proteins, inhibitors that block formation of these SSB protein complexes have great potential as novel anti-bacterial agents. The ultimate goals of this proposal are to elucidate the structures of ssDNA/SSB substrates, to reveal how enzymes take advantage of direct binding to SSB to process these structures, and to characterize the anti-bacterial properties of inhibitors that block heterologous protein association with SSB. The proposal brings together biochemical, structural, and genetic approaches to address these questions. PUBLIC HEALTH RELEVANCE: Genome maintenance processes ensure the accuracy of genetic information in cells and provide mechanisms whereby this information can be faithfully duplicated and distributed to daughter cells. These are essential process for all cells and require precise coordinate of many different proteins. This proposal aims to understand how several of these protein components are coordinated in cells and to investigate the anti-bacterial mechanisms of inhibitors that selectively block this coordination in bacteria.