Department of Biology, New York University, 100 Washington Square East, New York, NY, 10003, USA.
Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003, USA.
DNA Repair (Amst). 2018 May;65:73-78. doi: 10.1016/j.dnarep.2018.02.009. Epub 2018 Mar 8.
How DNA lesions in nucleosomes are recognized for global genome nucleotide excision repair (GG-NER) remains poorly understood, and the roles that histone tails may play remains to be established. Histone H3 and H4 N-terminal tails are of particular interest as their acetylation states are important in regulating nucleosomal functions in transcription, replication and repair. In particular the H3 tail has been the focus of recent attention as a site for the interaction with XPC, the GG-NER lesion recognition factor. Here we have investigated how the structure and dynamics of the DNA lesion cis-B[a]P-dG, derived from the environmental carcinogen benzo[a]pyrene (B[a]P), is impacted by the presence of flanking H3 and H4 tails. This lesion is well-repaired by GG-NER, and adopts a base-displaced/intercalated conformation in which the lesion partner C is displaced into the major groove. We used molecular dynamics simulations to obtain structural and dynamic characterizations for this lesion positioned in nucleosomal DNA so that it is bracketed by the H3 and H4 tails. The H4 tail was studied in unacetylated and acetylated states, while the H3 tail was unacetylated, its state when it binds XPC (Kakumu, Nakanishi et al., 2017). Our results reveal that upon acetylation, the H4 tail is released from the DNA surface; the H3 tail then forms a pocket that induces flipping and capture of the displaced lesion partner base C. This reveals synergistic effects of the behavior of the two tails. We hypothesize that the dual capability of the H3 tail to sense the displaced lesion partner base and to bind XPC could foster recognition of this lesion by XPC for initiation of GG-NER in nucleosomes.
组蛋白 H3 和 H4 N 端尾部特别有趣，因为它们的乙酰化状态在转录、复制和修复过程中调节核小体功能方面发挥着重要作用。特别是 H3 尾部，由于它是与 GG-NER 损伤识别因子 XPC 相互作用的部位，所以成为了最近关注的焦点。在这里，我们研究了环境致癌剂苯并[a]芘（B[a]P）衍生的 DNA 损伤顺式-B[a]P-dG 的结构和动力学如何受到侧翼 H3 和 H4 尾部的影响。这种损伤由 GG-NER 很好地修复，并采用碱基位移/嵌入构象，其中损伤伴侣 C 被位移到主槽中。我们使用分子动力学模拟来获得该损伤在核小体 DNA 中的结构和动态特征，以便它被 H3 和 H4 尾部所包围。研究了未乙酰化和乙酰化状态的 H4 尾部，而 H3 尾部未乙酰化，它与 XPC 结合时的状态（Kakumu、Nakanishi 等人，2017 年）。我们的结果表明，乙酰化后，H4 尾部从 DNA 表面释放；然后 H3 尾部形成一个口袋，诱导移位的损伤伴侣碱基 C 的翻转和捕获。这揭示了两条尾部行为的协同效应。我们假设 H3 尾部既能感知移位的损伤伴侣碱基，又能与 XPC 结合，这可能促进 XPC 识别这种损伤，从而启动核小体中的 GG-NER。
