The interplay of supercoiling and thymine dimers in DNA

Abstract

Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations, questions of how DNA supercoiling affects local defect properties, or, conversely, how the presence of such defects changes global supercoiled structure, are largely unexplored. Here, we introduce a model of thymine dimers in the oxDNA forcefield, parametrized by comparison to melting experiments and structural measurements of the thymine dimer induced bend angle. We performed extensive molecular dynamics simulations of double-stranded DNA as a function of external twist and force. Compared to undamaged DNA, the presence of a thymine dimer lowers the supercoiling densities at which plectonemes and bubbles occur. For biologically relevant supercoiling densities and forces, thymine dimers can preferentially segregate to the tips of the plectonemes, where they enhance the probability of a localized tip-bubble. This mechanism increases the probability of highly bent and denatured states at the thymine dimer site, which may facilitate repair enzyme binding. Thymine dimer-induced tip-bubbles also pin plectonemes, which may help repair enzymes to locate damage. We hypothesize that the interplay of supercoiling and local defects plays an important role for a wider set of DNA damage repair systems.

Structural interplay between DNA-shape protein recognition and supercoiling: The case of IHF

“…Overall, our simulations support the view that IHF function consists basically of organizing DNA into unique conformations in order to facilitate the types of genetic transactions in which the protein is involved. Interestingly, a similar plectoneme-pinning effect has also been detected in damaged DNA [74] , [75] , showing that local changes in DNA curvature and flexibility are key to regulating the folding of supercoiled loops. This together with the fact that IHF can be functionally replaced by other DNA-bending proteins [70] suggest that the positioning of plectonemes might be a general principle for this type of architectural proteins.…”

Two Different Ways of Stress Release in Supercoiled DNA Minicircles under DNA Nick

“…The relaxation of the DNA occurs due to the breakage. To study both the change of structure and the dynamical evolution, we adopt the oxDNA2 model, − which was used in DNA hairpin, − supercoiled DNA, − and DNA nanotechnology, − to provide information on the molecular level. In our model, the circular DNA is composed of 336 bp, i.e., 672 nucleotides.…”

Correlated Hybrid DNA Structures Explored by the oxDNA Model

“…The system we investigated focuses on the process of DNA hybridization in DNA microarrays. In order to examine both structural changes and dynamic evolution, we utilize the oxDNA2 model. − This particular model has been extensively employed in studying various aspects such as DNA hybridization, DNA hairpin formation, − supercoiled DNA, − and DNA nanotechnology, − enabling insights at the molecular level. In our model, each probe or target consists of 20 nucleotides.…”