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Program
Craig Benham, Mathematics, Biomedical Engineering, and the UC Davis Genome Center, UC Davis
Topologically Driven Structural Transitions in DNA - Their Analysis and Roles in Biology
DNA within cells is topologically constrained into a series of loops. This fixes the linking number Lk of each loop, the number of times either strand of the DNA duplex links through the closed loop formed by the other strand. The value of Lk is stringently controlled by processes involving transient strand breaks. This in turn regulates the stresses imposed on the DNA within individual loops. Untwisting torsional stresses can destabilize the DNA duplex, causing its strands to separate at specific positions where the thermodynamic stability is low. This phenomenon is is complicated to analyze because the topological constraint globally couples together the transition behaviors of all the base pairs in the loop. It is biologically important because strand separation is an obligatory step in the initiation of both replication and gene expression, the two main jobs of DNA.
This talk will briefly describe how DNA is topologically constrained, and how this constraint is regulated within cells. A mathematical method will be described to analyze the strand separation transition within DNA loops where Lk is fixed. This method performs a formally exact statistical mechanical calculation of the equilibrium distribution of a population of identical DNA loops among all the available conformational states. The energy and conformational parameners used in this analysis are all taken from experimental measurements, so there are no free parameters in this model. Yet when it is applied to the analysis of specific DNA sequences, the results of this method are in quantitatively precise agreement with experimental measurements of the locations and extents of local strand separations. This justifies its use to predict the duplex destabilization properties of other DNA base sequences, on which experiments have not been performed.
The sites of predicted duplex destabilization within natural DNA sequences do not occur at random, but instead are closely associated with specific types of DNA regulatory elements. Examples include sites controlling the initiation and termination of gene expression, origins of replication, and positions where the DNA is attached to the chromosomal matrix. Several cases have been documented where this stress-induced duplex destabilization participates in the mechanisms of function of specific regulatory elements. A selection of predictions of the destabilization properties of regulatory regions will be presented, as time permits. The results from experiments that were performed to test these predictions will also be described.