Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan.
Ph.D. Program in Medical Biotechnology, National Chung Hsing University, Taichung, 402, Taiwan.
Nucleic Acids Res. 2019 Sep 19;47(16):8899-8912. doi: 10.1093/nar/gkz653.
DNA mismatches are highly polymorphic and dynamic in nature, albeit poorly characterized structurally. We utilized the antitumour antibiotic CoII(Chro)2 (Chro = chromomycin A3) to stabilize the palindromic duplex d(TTGGCGAA) DNA with two G:G mismatches, allowing X-ray crystallography-based monitoring of mismatch polymorphism. For the first time, the unusual geometry of several G:G mismatches including syn-syn, water mediated anti-syn and syn-syn-like conformations can be simultaneously observed in the crystal structure. The G:G mismatch sites of the d(TTGGCGAA) duplex can also act as a hotspot for the formation of alternative DNA structures with a GC/GA-5' intercalation site for binding by the GC-selective intercalator actinomycin D (ActiD). Direct intercalation of two ActiD molecules to G:G mismatch sites causes DNA rearrangements, resulting in backbone distortion to form right-handed Z-DNA structures with a single-step sharp kink. Our study provides insights on intercalators-mismatch DNA interactions and a rationale for mismatch interrogation and detection via DNA intercalation.
DNA 错配在性质上高度多态且动态，但结构上的特征描述较差。我们利用抗肿瘤抗生素 CoII(Chro)2（Chro = 色霉素 A3）稳定具有两个 G:G 错配的回文双链 d(TTGGCGAA)DNA，允许基于 X 射线晶体学的错配多态性监测。首次可以在晶体结构中同时观察到几种 G:G 错配的异常几何形状，包括顺-顺、水介导的反-顺和类似顺-顺的构象。d(TTGGCGAA)双链的 G:G 错配位点也可以作为形成其他 DNA 结构的热点，具有 GC/GA-5' 嵌入位点，可与 GC 选择性嵌入剂放线菌素 D (ActiD)结合。两个 ActiD 分子直接插入 G:G 错配位点会导致 DNA 重排，导致骨架扭曲形成具有单步尖锐拐点的右手 Z-DNA 结构。我们的研究提供了关于嵌入剂-错配 DNA 相互作用的见解，并为通过 DNA 嵌入进行错配检测提供了依据。
