Control of elongation of DNA replication

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DESCRIPTION (provided by applicant): Accurate and complete DNA replication is of paramount importance for all organisms. Replication elongation is highly susceptible to disruptions leading to fateful consequences including incomplete replication, mutations and genome rearrangements, which can underlie cell death, genomic disorders, tumor formation and progression. Despite the importance of minimizing disruption of DNA replication elongation, how cells manage to do so remains poorly understood. We recently employed genome-wide, systematic approaches to identify a novel nutrient-responsive regulation of replication elongation in the Gram-positive bacterium Bacillus subtilis. We propose that this regulation keeps replication elongation under metabolic control to prevent disruption of replication, and together with mechanisms that rescue and reactivate the disrupted replication forks, maintains genome integrity robustly. Such mechanisms are likely to exist in other organisms and play far more important roles than previously conceived. We aim to evaluate the role of regulation of replication elongation, its prevalence in other bacteria such as E. coli, and to define the molecular differences between regulated replication arrests and disruptive replication arrests. Our study will contribute significantly to knowledge of the connection between the replication elongation complex and its cellular environment. This will deepen the understanding of the possible roles of uncontrolled replication in tumorigenesis and genomic disorders and elucidate fundamental principles underlying genome integrity. The specific aims are: 1. Examine the role of a novel regulatory mechanism of replication elongation in B. subtilis; 2. Characterize key events at replication forks following diverse replication arrests; 3. Characterize the control of replication elongation in E. coli. PUBLIC HEALTH RELEVANCE: We discovered a new way that bacteria control duplication of their DNA. Investigating this pathway elucidates novel and conserved principles of control of DNA duplication. Loss of this control potentially leads to genome rearrangements and mutagenesis, which underlies several human genomic disorders and cancers. Understand this pathway is also important for understanding microbial development of antibiotic resistance.