In response to DNA damage, most factors involved in damage recognition and repair are tightly regulated to ensure proper repair pathway choice. Histone acetylation at DNA double strand breaks (DSBs) by p300 histone acetyltransferase (HAT) is critical for the recruitment of DSB repair proteins to chromatin. Here, we show that phosphorylation of Sp1 by ATM increases its interaction with p300 and that Sp1-dependent recruitment of p300 to DSBs is necessary to modify the histones associated with p300 activity and NHEJ repair factor recruitment and repair. p300 is known to acetylate multiple residues on histones H3 and H4 necessary for NHEJ. Acetylation of H3K18 by p300 is associated with the recruitment of the SWI/SNF chromatin remodeling complex and Ku70 to DSBs for NHEJ repair. Depletion of Sp1 results in decreased acetylation of lysines on histones H3 and H4. Specifically, cells depleted of Sp1 display defects in the acetylation of H3K18, resulting in defective SWI/SNF and Ku70 recruitment to DSBs. These results shed light on mechanisms by which chromatin remodelers are regulated to ensure activation of the appropriate DSB repair pathway.

为了应对 DNA 损伤，涉及损伤识别和修复的大多数因素都受到严格调控，以确保正确的修复途径选择。 p300 组蛋白乙酰转移酶 (HAT) 对 DNA 双链断裂 (DSB) 的组蛋白乙酰化对于将 DSB 修复蛋白募集到染色质至关重要。在这里，我们表明，ATM 对 Sp1 的磷酸化增加了其与 p300 的相互作用，并且 Sp1 依赖性 p300 向 DSB 的募集对于修饰与 p300 活性和 NHEJ 修复因子募集和修复相关的组蛋白是必要的。已知 p300 可以乙酰化 NHEJ 必需的组蛋白 H3 和 H4 上的多个残基。 p300 对 H3K18 的乙酰化与 SWI/SNF 染色质重塑复合物和 Ku70 募集至 DSB 以进行 NHEJ 修复相关。 Sp1 的耗尽会导致组蛋白 H3 和 H4 上赖氨酸的乙酰化降低。具体来说，Sp1 耗尽的细胞在 H3K18 乙酰化方面表现出缺陷，导致 SWI/SNF 和 Ku70 招募到 DSB 时出现缺陷。这些结果揭示了染色质重塑剂的调节机制，以确保适当的 DSB 修复途径的激活。