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首页> 外文期刊>ACS catalysis >Electron Fate and Mutational Robustness in the Mechanism of (6-4)Photolyase-Mediated DNA Repair
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Electron Fate and Mutational Robustness in the Mechanism of (6-4)Photolyase-Mediated DNA Repair

机译：电子命运和突变鲁棒性在（6-4）光解酶介导的DNA修复机制中

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摘要

UV radiation triggers the formation of an adjacent pyrimidine lesion in DNA, pyrimidine(6-4)pyrimidone photoproduct ((6-4)PP). These lesions are cytotoxic and interfere with cell replication and transcription, eventually inducing apoptosis, but they are readily repaired by (6-4)photolyase. However, the details of the repair mechanism have been debated. Here, we describe the mechanism of the photorepair cycle, the roles of the active site His365 and His369 residues, and the robustness against mutation of these residues. Using molecular dynamics simulations, quantum mechanical/molecular mechanical (QM/MM) calculations, large-QM/MM which includes 982 atoms in the QM layer, Marcus theory, and Fourier transform infrared (FTIR) spectroscopic measurements, we found that an electron is first transferred to the 5'-base of (6-4)PP to form a radical; subsequently a proton transfer from His365 to (6-4)PP causes water formation, which induces further OH transfer upon water activation and ultimately DNA repair. A H365A mutant repairs (6-4)PP similarly, with His369 compensating for His365 through a 3'-base radical. Our findings also provide an explanation of the observed low quantum yield in the wild-type and mutant proteins.
机译：UV辐射触发DNA中相邻嘧啶病变的形成，嘧啶（6-4）嘧啶光调节（（6-4）pp）。这些病变是细胞毒性，干扰细胞复制和转录，最终诱导细胞凋亡，但它们被（6-4）光解酶易于修复。但是，修复机制的细节已经讨论。在这里，我们描述了光源循环的机制，活性位点His365和His369残基的作用以及对这些残留物的突变的鲁棒性。使用分子动力学模拟，量子机械/分子机械（QM / mm）计算，大QM / mm，包括QM层，Marcus理论和傅里叶变换红外（FTIR）光谱测量中的982个原子，我们发现电子是首先转移到（6-4）PP的5'-碱以形成自由基;随后，来自HIS365至（6-4）PP的质子转移导致水形成，其在水活化和最终DNA修复时诱导进一步OH转移。 H365A突变体维修（6-4）PP同样，HIS369通过A365通过3'-基础自由基来补偿HIS365。我们的研究结果还提供了对野生型和突变蛋白中观察到的低量子产量的解释。

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