Abstract
We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes.
Highlights
DNA often occurs in an underwound, negatively superhelical topological state in vivo
We present the stress-induced B-Z transitions (SIBZ) algorithm that calculates the equilibrium properties of the transition from right-handed B-form to left-handed Z-form in a DNA sequence that is subjected to imposed stresses
We show that the results produced by SIBZ agree closely with experimental observations of both the onset of transitions and the locations of Z-form sites in molecules of specified sequence
Summary
DNA often occurs in an underwound, negatively superhelical topological state in vivo. The dynamic balance between these two processes determines a basal level of superhelicity that can change according to the environmental or nutritional state of the organism [1]. RNA polymerase translocation leaves a wake of negative supercoils and generates a bow wave of positive supercoils [2,3,4]. Together these effects induce substantial amounts of superhelicity in the topological domains into which bacterial genomes are subdivided. A variety of regulatory processes in prokaryotes, including the initiation of transcription from specific genes, are known to vary with the level of superhelicity experienced by the DNA involved [5]
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