Department of Biochemistry, Kangwon National University, Chuncheon, 24341, South Korea.
Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
Chemistry. 2020 Nov 6;26(62):14181-14186. doi: 10.1002/chem.202002834. Epub 2020 Oct 1.
Cyclobutane pyrimidine dimer (CPD) is a photoproduct formed by two stacked pyrimidine bases through a cycloaddition reaction upon irradiation. Owing to its close association with skin cancer, the mechanism of CPD formation has been studied thoroughly. Among many aspects of CPD, its formation involving 5-methylcytosine (5mC) has been of special interest because the CPD yield is known to increase with C5-methylation of cytosine. In this work, high-level quantum mechanics/molecular mechanics (QM/MM) calculations are used to examine a previously experimentally detected pathway for CPD formation in hetero (thymine-cytosine and thymine-5mC) dipyrimidines, which is facilitated through intersystem crossing in thymine and formation of a triplet biradical intermediate. A DNA duplex model system containing a core sequence TmCG or TCG is used. The stabilization of a radical center in the biradical intermediate by the methyl group of 5mC can lead to increased CPD yield in TmCG compared with its non-methylated counterpart, TCG, thereby suggesting the existence of a new pathway of CPD formation enhanced by 5mC.
环丁烷嘧啶二聚体（CPD）是一种光产物，由两个堆叠的嘧啶碱基通过环加成反应形成，在照射下形成。由于其与皮肤癌密切相关，因此已对 CPD 形成的机制进行了深入研究。在 CPD 的许多方面中，涉及 5-甲基胞嘧啶（5mC）的形成特别受到关注，因为据知 CPD 的产量会随着胞嘧啶的 C5-甲基化而增加。在这项工作中，使用高级量子力学/分子力学（QM/MM）计算来检查先前在异（胸腺嘧啶-胞嘧啶和胸腺嘧啶-5mC）二嘧啶中检测到的 CPD 形成途径，该途径通过胸腺嘧啶中的系间窜跃和三重态双自由基中间体的形成来促进。使用包含核心序列 TmCG 或 TCG 的 DNA 双链模型系统。5mC 的甲基可以稳定双自由基中间体中的自由基中心，从而导致 TmCG 中的 CPD 产量增加，与非甲基化的 TCG 相比，从而表明存在由 5mC 增强的新的 CPD 形成途径。
