The first order of DNA packaging is the nucleosome with the DNA wrapped around the histone octamer. This leaves the nucleosomal DNA with access restrictions, which impose a significant barrier to repair of damaged DNA. The efficiency of DNA repair has been related to nucleosome structure and chromatin status, which is modulated in part by post-translational modifications (PTMs) of histones. Numerous studies have suggested a role for acetylation of lysine at position 56 of the H3 histone (H3K56ac) in various DNA transactions, including the response to DNA damage and its association with human cancer. Biophysical studies have revealed that H3K56ac increases DNA accessibility by facilitating spontaneous and transient unwrapping motions of the DNA ends. However, how this acetylation mark modulates nucleosome structure and dynamics to promote accessibility to the damaged DNA for repair factors and other proteins is still poorly understood. Here, we utilize approximately 5–6 microseconds of atomistic molecular dynamics simulations to delineate the impact of H3K56 acetylation on the nucleosome structure and dynamics, and to elucidate how these nucleosome properties are further impacted when a bulky benzo[a]pyrene-derived DNA lesion is placed near the acetylation site. Our findings reveal that H3K56ac alone induces considerable disturbance to the histone-DNA/histone-histone interactions, and amplifies the distortions imposed by the presence of the lesion. Our work highlights the important role of H3K56 acetylation in response to DNA damage and depicts how access to DNA lesions by the repair machinery can be facilitated within the nucleosome via a key acetylation event.

DNA 包装的第一顺序是核小体，DNA 包裹在组蛋白八聚体周围。这使得核小体 DNA 受到限制，这对修复受损 DNA 构成了重大障碍。DNA 修复的效率与核小体结构和染色质状态有关，这部分受到组蛋白翻译后修饰 (PTM) 的调节。大量研究表明 H3 组蛋白 (H3K56ac) 的 56 位赖氨酸乙酰化在各种 DNA 交易中的作用，包括对 DNA 损伤的反应及其与人类癌症的关联。生物物理学研究表明，H3K56ac 通过促进 DNA 末端的自发和瞬时展开运动来增加 DNA 的可及性。然而，这种乙酰化标记如何调节核小体结构和动力学以促进修复因子和其他蛋白质对受损 DNA 的可及性仍然知之甚少。在这里，我们利用大约 5-6 微秒的原子分子动力学模拟来描述 H3K56 乙酰化对核小体结构和动力学的影响，并阐明当笨重的苯并[a ] 芘衍生的 DNA 损伤位于乙酰化位点附近。我们的研究结果表明，单独的 H3K56ac对组蛋白-DNA/组蛋白-组蛋白相互作用产生了相当大的干扰，并放大了由病变存在造成的扭曲。我们的工作强调了 H3K56 乙酰化在应对 DNA 损伤中的重要作用，并描述了如何通过关键的乙酰化事件在核小体内促进修复机制进入 DNA 损伤。