Molecular Noise, Transcription Errors and Heritable Phenotypic Change

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 DESCRIPTION (provided by applicant): Errors in information transfer from DNA to RNA to protein are inevitable. Transcription errors occur at a rate of ~10-5 per residue in Escherichia coli, over 10,000 times higher than errors in DNA synthesis. Errors in DNA synthesis can produce heritable changes in phenotype due to alteration of protein function. Studies that have focused on the mechanisms of DNA replication and repair in E. coli have provided a major framework for understanding the fidelity of genetic transmission from cell to cell and have revealed a series of fidelity mechanisms responsible for maintaining DNA integrity. Transcription errors, although transient in nature, can also have phenotypic consequences for the cell, including transient and heritable phenotypic change. Unlike DNA fidelity, the mechanisms ensuring transcription fidelity in vivo are not well characterized due to the difficulty of isolatig such transient errors in mRNA. The overall goal of this research is to (1) define the origins and the consequences of transcription errors in Escherichia coli, and (2) study the conflict between transcription fidelity and DNA repair. We have developed novel genetic tools to capture transcription errors and study their effect at the cellular level. Using next generation sequencing we will identify the spectrum of transcription errors and monitor how transcription fidelity hinder DNA break repair. This work will illuminate the fundamental cell/molecular biology of transcription fidelity in living cells, which are likely to be critical to many fundamental aspectsof biology and medicine including cancer, aging, and the resistance to drugs such as antibiotics.