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• W2249272810 abstract "tmRNA is known to play a role in translational quality control in all bacteria, but the phenotypes of cells lacking tmRNA suggest that the tmRNA pathway is integrated into the global regulatory network. The tmRNA pathway is important for both bacterial physiology and bacterial pathogenesis. To understand the physiological role of tmRNA in bacteria, and to exploit tmRNA as a target for antibiotics, we investigated the activity of tmRNA in the model species Caulobacter crescentus. In C. crescentus lacking tmRNA activity, initiation of DNA replication is delayed. To understand the molecular basis of the tmRNA phenotype, the impacts of tmRNA activity on the expression of replication initiator protein DnaA, and the transcription from a strong promoter (Ps) within the origin were investigated. We demonstrated that transcription of dnaA and Ps are both delayed in cells lacking tmRNA activity. We identified a TCAA motif from the dnaA promoter that is important for the timing of dnaA transcription. A possible model is that tmRNA can regulate an unknown transcriptional regulator, and the unknown transcriptional regulator could bind to the TCAA motif in both the PdnaA and Ps, thereby regulating the timing of transcription from both and ensuring the correct timing of DNA replication initiation. We also showed that the 5?UTR of dnaA strongly represses dnaA expression. Although this repression is not tmRNA-dependent, it could be a conserved mechanism on dnaA regulation in other bacteria. Because tmRNA is essential for viability or virulence in many species, inhibitors of the tmRNA pathway could have bactericidal activity. We developed genetic methods to screen libraries of cyclic peptides for inhibitors of individual steps in the tmRNA pathway, and had isolated cyclic peptides that inhibit the proteolysis of tmRNA-tagged proteins in E. coli. Inhibitors shared little sequence similarity and interfered with various steps in the ClpXP mechanism in vitro. Several of these inhibitors were bactericidal when added exogenously to cultures of C. crescentus, which that requires ClpXP activity for viability. This result suggests that the tmRNA pathway may be a useful target for antibiotic development." @default.
• W2249272810 created "2016-06-24" @default.
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• W2249272810 date "2008-06-20" @default.
• W2249272810 modified "2023-09-27" @default.
• W2249272810 title "Role of the tmRNA pathway in bacterial physiology and its use in antibiotic development" @default.
• W2249272810 hasPublicationYear "2008" @default.
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