Regulation of lambda dv plasmid DNA replication. A quantitative model for control of plasmid lambda dv replication in the bacterial cell division cycle.

A quantitative model for the regulation of replication of plasmid lambda dv in the Escherichia coli cell division cycle has been developed. The regulatory processes include the interactions of cro repressor proteins with the rightward operator DNA sites, the transcriptional activation of the lambda dv replication origin, and the interaction of initiation proteins with activated origins to form functional replication initiation complexes. A statistical thermodynamic model was used to predict probable configurations of the regulatory processes in a single growing cell. These probabilities were coupled by a kinetic model to the events of the cell cycle such as initiation of mRNA transcription and protein translation and the initiation of plasmid DNA replication. Parameter values were chosen so that the simulated values for plasmid copy number and repressor and initiator protein concentrations of the model agreed with experimentally determined estimates. Simulated deviations from regular segregation of the various components at cell division, such as plasmid copies and free and bound repressor proteins, suggest that lambda dv replication control responds only slowly to these perturbations. The consequence of this slow response to perturbations, which are expected at a random frequency, was simulated for a population of lambda dv-containing cells in a growing culture. This simulation predicts instability of inheritance of lambda dv plasmids in the population, despite the very high plasmid copy number, in agreement with experimental observation.