Dršata Tomáš, Kara Mahmut, Zacharias Martin, Lankaš Filip
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Flemingovo náměstı́ 2, 166 10, Praha 6, Czech Republic.
J Phys Chem B. 2013 Oct 3;117(39):11617-22. doi: 10.1021/jp407562t. Epub 2013 Sep 20.
8-Oxoguanine (oxoG) is an abundant product of oxidative DNA damage. It is removed by repair glycosylases, but exactly how the enzymes recognize oxoG in the large surplus of undamaged bases is not fully understood. The lesion may induce changes in the properties of naked DNA that facilitate the recognition. In this work, we assess the effect of oxoG on DNA structure and mechanical deformability. We performed extensive unrestrained, atomic resolution molecular dynamics simulations to parametrize a nonlocal, rigid base mechanical model of DNA. Our data indicate that oxoG induces unwinding of the base pair step at the 5'-side of the lesion. This brings the damaged DNA closer to its conformation in the initial complex with bacterial glycosylase MutM. The untwisting is partially caused by different BII substate populations and is further enhanced by the base-sugar repulsion within oxoG. On the other hand, our analysis shows that damaged and undamaged DNA have very similar harmonic stiffness. These results suggest an indirect readout component of the MutM-DNA initial complex formation. They also help one to understand the effect of oxoG on the formation of nucleosomes and looped gene regulatory complexes.
8-氧代鸟嘌呤（oxoG）是氧化性DNA损伤的一种常见产物。它可被修复糖基化酶去除，但这些酶究竟如何在大量未受损碱基中识别oxoG尚不完全清楚。该损伤可能会诱导裸露DNA性质发生变化，从而便于识别。在这项研究中，我们评估了oxoG对DNA结构和机械变形能力的影响。我们进行了广泛的无约束原子分辨率分子动力学模拟，以参数化DNA的非局部刚性碱基力学模型。我们的数据表明，oxoG会诱导损伤位点5'侧的碱基对步解开。这使得受损DNA更接近其与细菌糖基化酶MutM形成初始复合物时的构象。这种解旋部分是由不同的BII亚态群体引起的，并因oxoG内的碱基-糖排斥作用而进一步增强。另一方面，我们的分析表明，受损和未受损的DNA具有非常相似的谐性刚度。这些结果表明了MutM-DNA初始复合物形成过程中的间接读出成分。它们也有助于人们理解oxoG对核小体和环状基因调控复合物形成的影响。
