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"Shea, Adele"
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A QUANTITATIVE MODEL OF GENE REGULATION: CONTROL OF BACTERIOPHAGE LAMBDA OPERATORS BY REPRESSOR PROTEINS (COOPERATIVITY, THERMODYNAMICS, DNA, DEOXYRIBONUCLEIC ACID)
A quantitative model for the dynamic processes that regulate gene expression has been developed; this model has been applied to the bacteriophage lambda O(,R)/O(,L) switch that maintains stable lysogenic growth and drives the irreversible transition to viral replication and cell lysis. The model has two major components: (a) A statistical thermodynamic theory incorporates protein-DNA interaction energies into an expression for the probability of each of the various configurations of repressor proteins and RNA polymerase bound at the three-site control regions, O(,R) and O(,L), and their overlapping promoters P(,R), P/(,RM), and P(,L); (b) A kinetic model couples these probabilities to the net production of three transcriptional control proteins, cI repressor, cro and N. During induction of lysis when cI repressor is specifically degraded by recA, the model was found to predict a burst of cro and N protein synthesis followed by a turnoff of early genes by cro. This was one of several features that were not explicitly programmed into the model. The simulations of protein synthesis demonstrated how the equilibrium between ligands vying for the same genomic sites but with different affinities could precisely synchronize physiological behavior. We investigated response characteristics of the system by altering the balance between equilibrium and kinetic properties, cooperative and catalytic interactions, and showed how their presence stabilized the prophage, while their absence contributed to virulence. We have also introduced specific mutations into the system by altering one or a few parameters and stimulated the protein levels. This model and the results obtained through its use demonstrate a powerful approach to understanding how complex dynamic properties in genomic regulatory systems may arise from fundamental interactions among the molecular constituents. The success of the model to predict physiological characteristics for mutant and wild-type phage provides support for the underlying physico-chemical assumptions used in its formulation.
Dissertation