Optimal DNA damage response is associated with ADP‐ribosylation of histones. However, the underlying molecular mechanism of DNA damage‐induced histone ADP‐ribosylation remains elusive. Herein, using unbiased mass spectrometry, we identify that glutamate residue 141 (E141) of variant histone H2AX is ADP‐ribosylated following oxidative DNA damage. In‐depth studies performed with wild‐type H2AX and the ADP‐ribosylation‐deficient E141A mutant suggest that H2AX ADP‐ribosylation plays a critical role in base excision repair (BER). Mechanistically, ADP‐ribosylation on E141 mediates the recruitment of Neil3 glycosylase to the sites of DNA damage for BER. Moreover, loss of this ADP‐ribosylation enhances serine‐139 phosphorylation of H2AX (γH2AX) upon oxidative DNA damage and erroneously causes the accumulation of DNA double‐strand break (DSB) response factors. Taken together, these results reveal that H2AX ADP‐ribosylation not only facilitates BER repair, but also suppresses the γH2AX‐mediated DSB response.

中文翻译：

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组蛋白变体 H2AX 的 ADP-核糖基化促进碱基切除修复


最佳 DNA 损伤反应与组蛋白的 ADP 核糖基化相关。然而，DNA 损伤诱导组蛋白 ADP 核糖基化的潜在分子机制仍然难以捉摸。在此，使用无偏质谱法，我们鉴定出变体组蛋白 H2AX 的谷氨酸残基 141 (E141) 在 DNA 氧化损伤后发生 ADP 核糖基化。对野生型 H2AX 和 ADP-核糖基化缺陷 E141A 突变体进行的深入研究表明，H2AX ADP-核糖基化在碱基切除修复 (BER) 中发挥着关键作用。从机制上讲，E141 上的 ADP-核糖基化介导 Neil3 糖基化酶募集到 DNA 损伤位点以产生 BER。此外，这种 ADP-核糖基化的缺失会增强 DNA 氧化损伤时 H2AX (γH2AX) 的丝氨酸-139 磷酸化，并错误地导致 DNA 双链断裂 (DSB) 反应因子的积累。综上所述，这些结果表明 H2AX ADP 核糖基化不仅促进 BER 修复，而且抑制 γH2AX 介导的 DSB 响应。