Sequence-dependent response of DNA to torsional stress: a potential biological regulation mechanism.

Anna Reymer,Richard Lavery,Krystyna Zakrzewska

doi:10.1093/nar/gkx1270

Abstract

Torsional restraints on DNA change in time and space during the life of the cell and are an integral part of processes such as gene expression, DNA repair and packaging. The mechanical behavior of DNA under torsional stress has been studied on a mesoscopic scale, but little is known concerning its response at the level of individual base pairs and the effects of base pair composition. To answer this question, we have developed a geometrical restraint that can accurately control the total twist of a DNA segment during all-atom molecular dynamics simulations. By applying this restraint to four different DNA oligomers, we are able to show that DNA responds to both under- and overtwisting in a very heterogeneous manner. Certain base pair steps, in specific sequence environments, are able to absorb most of the torsional stress, leaving other steps close to their relaxed conformation. This heterogeneity also affects the local torsional modulus of DNA. These findings suggest that modifying torsional stress on DNA could act as a modulator for protein binding via the heterogeneous changes in local DNA structure.

Highlights

Understanding how the underlying organization of genome contributes to biological regulation is an important question
One important element in this organization is linked to the torsional strain that is imposed on the DNA double helix by many essential biological processes
As a preliminary test of how DNA responds to torsional stress in a sequence-dependent manner, we present results on four 17 bp oligomers, whose central segments contain repeat sequences involving the tetranucleotides ACGT, ACGA, CCGA and AGCT

Summary

Introduction

Understanding how the underlying organization of genome contributes to biological regulation is an important question. One important element in this organization is linked to the torsional strain that is imposed on the DNA double helix by many essential biological processes This strain leads to supercoiling, namely axial bending combined with overor undertwisting, and potentially to the formation of interwound plectonemic structures. One example of such a process is transcription where immobilized RNA polymerase within transcription factories forces DNA to rotate around its axis as the double helix threads through the transcription machinery [1,2]. Modifying supercoiling will impact chromatin structure at many scales, locally modifying DNA conformation (notably, bending and twisting), stabilizing or destabilizing nucleosome core particles [4], and changing higher-order chromatin structures, with a resultant impact on protein–DNA interactions [5]

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