期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 5, 页码 2480-2492出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac082
关键词
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资金
- Engineering and Physical Sciences Research Council [EP/F500394/1]
- Oxford Physics Endowment for Graduates
- Oxford University's RCUK Open Access Block Grant
Thymine dimers are found to affect the supercoiling of DNA, causing changes in the occurrence of plectonemes and bubbles. The presence of thymine dimers increases the probability of localized tip-bubbles, facilitating repair enzyme binding and damage repair. The interplay between supercoiling and local defects plays an important role in DNA damage repair systems.
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.
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