Mutational Analysis of E. Coli Core RNA Polymerase

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Our fundamental interest is the central biological problem of how a cell regulates transfer of information from genes to proteins. Our goal is to understand the decision making process that underlies the transcriptional output of RNA polymerase (RNAP). In prokaryotic organisms, the cellular repertoire of sigmas orchestrate transcription initiation and constitute a major input to the decision-making process. We will probe the relationship between sigma input and RNAP output at levels ranging from the molecular to the genomic. During the current granting period, we will: 1. Critically define the role of sigma in melting promoterDMA. 2. Define common and unique functional aspects of sigma groups. 3. Assess cellular readout of RNA polymerase status. 4. Investigate the evolution of alternative sigma's and their regulons in distantly related genomes. These studies determine the fundamental contributions of sigma's to transcription, identify differences between the sigma subfamilies, develop the methodology to predict promoters and to understand how altering the status of holoenzyme is translated into cellular regulatory circuits. Such information could be used to design new drugs that specifically target bacterial processes. Given the conservation of bacterial holoenzyme, our results will inform studies of all bacteria, including pathogens and bidterrorism hazards. Moreover, the questions we are asking and the methods we are developing will allow us to use the vast genomic information now available to understand other bacteria that may be difficult or even impossible to study experimentally.