The interplay of supercoiling and thymine dimers in DNA.

Wilber Lim, Ferdinando Randisi, Jonathan P K Doye, Ard A Louis

Nucleic acids research 2022 Mar 21

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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. © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

Citation

Wilber Lim, Ferdinando Randisi, Jonathan P K Doye, Ard A Louis. The interplay of supercoiling and thymine dimers in DNA. Nucleic acids research. 2022 Mar 21;50(5):2480-2492