Oxidative damage to DNA is widely known to contribute to aging and disease. This relationship has been extensively studied for telomeres - structures that cap chromosome ends - due to their role in cell proliferation and senescence, and exceptional susceptibility to oxidation. Indeed, the repetitive telomeric DNA sequence contains the 5'-GGG-3' motif that has the lowest ionization potential of all trinucleotides. Accordingly, experiments consistently show that telomeric oxidative lesions are more abundant and persistent than elsewhere in the genome. This led to a hypothesis that telomeres act as sensors of prolonged oxidative stress and prevent carcinogenesis, as disruption of telomeric integrity triggers senescence or apoptosis. Here, we use atomistic alchemical Molecular Dynamics simulations to perform a combinatorial assessment of changes in DNA binding affinity of telomeric proteins induced by oxidative guanine lesions. We rank lesions by their effect on telomere integrity, as well as telomeric proteins by their sensitivity to DNA oxidation. While the binding of most proteins is abolished by DNA oxidation, HOT1 emerges as a notable exception, suggesting its potential role in sensing of oxidative damage. Through statistical analysis and free energy decomposition, we also identify common trends in structural responses of protein-DNA complexes that contribute to decreased binding affinity.

中文翻译：

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常见的氧化鸟嘌呤损伤端粒解开：原子模型的见解。

众所周知，DNA的氧化损伤会导致衰老和疾病。由于端粒在细胞增殖和衰老中的作用以及对氧化的异常敏感性，因此对端粒-染色体末端加帽的结构-进行了广泛的研究。实际上，重复的端粒DNA序列含有5'-GGG-3'基序，其在所有三核苷酸中具有最低的电离势。因此，实验一致表明端粒氧化损伤比基因组中的其他部位更丰富和持久。这导致一个假设，即端粒充当长期氧化应激的传感器并阻止癌变，因为端粒完整性的破坏会引发衰老或凋亡。这里，我们使用原子化学炼金术分子动力学模拟来执行氧化鸟嘌呤损伤诱导端粒蛋白的DNA结合亲和力变化的组合评估。我们根据病变对端粒完整性的影响对病变进行分类，并根据对DNA氧化的敏感性对端粒蛋白进行分类。虽然大多数蛋白质的结合被DNA氧化所消除，但HOT1作为一个显着例外出现，表明其在感知氧化损伤中的潜在作用。通过统计分析和自由能分解，我们还确定了导致结合亲和力降低的蛋白质-DNA复合物结构响应的常见趋势。以及端粒蛋白对DNA氧化的敏感性。虽然大多数蛋白质的结合被DNA氧化所消除，但HOT1作为一个显着例外出现，表明其在感知氧化损伤中的潜在作用。通过统计分析和自由能分解，我们还确定了导致结合亲和力降低的蛋白质-DNA复合物结构响应的常见趋势。以及端粒蛋白对DNA氧化的敏感性。虽然大多数蛋白质的结合被DNA氧化所消除，但HOT1作为一个显着例外出现，表明其在感知氧化损伤中的潜在作用。通过统计分析和自由能分解，我们还确定了导致结合亲和力降低的蛋白质-DNA复合物结构响应的常见趋势。