Dehez François, Gattuso Hugo, Bignon Emmanuelle, Morell Christophe, Dumont Elise, Monari Antonio
CNRS, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.
Université de Lorraine, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.
Nucleic Acids Res. 2017 Apr 20;45(7):3654-3662. doi: 10.1093/nar/gkx148.
DNA photolesions constitute a particularly deleterious class of molecular defects responsible for the insurgence of a vast majority of skin malignant tumors. Dimerization of two adjacent thymines or cytosines mostly gives rise to cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone 64-PP as the most common defects. We perform all-atom classical simulations, up to 2 μs, of CPD and 64-PP embedded in a 16-bp duplex, which reveal the constrasted behavior of the two lesions. In particular we evidence a very limited structural deformation induced by CPD while 64-PP is characterized by a complex structural polymorphism. Our simulations also allow to unify the contrasting experimental structural results obtained by nuclear magnetic resonance or Förster Resonant Energy Transfer method, showing that both low and high bent structures are indeed accessible. These contrasting behaviors can also explain repair resistance or the different replication obstruction, and hence the genotoxicity of these two photolesions.
DNA光损伤构成了一类特别有害的分子缺陷，它们是绝大多数皮肤恶性肿瘤产生的原因。两个相邻胸腺嘧啶或胞嘧啶的二聚化大多会产生环丁烷嘧啶二聚体（CPD）和嘧啶（6-4）嘧啶酮（6-4-PP），这是最常见的缺陷。我们对嵌入16碱基对双链体中的CPD和6-4-PP进行了长达2微秒的全原子经典模拟，揭示了这两种损伤的不同行为。特别是，我们证明CPD引起的结构变形非常有限，而6-4-PP的特征是复杂的结构多态性。我们的模拟还能够统一通过核磁共振或Förster共振能量转移方法获得的相互矛盾的实验结构结果，表明低弯曲和高弯曲结构确实都有可能出现。这些不同的行为也可以解释修复抗性或不同的复制阻碍，从而解释这两种光损伤的遗传毒性。
