组蛋白变体 H2AX 的 ADP-ribosylation 促进碱基切除修复。
ADP-ribosylation of histone variant H2AX promotes base excision repair.
机构信息
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
出版信息
EMBO J. 2021 Jan 15;40(2):e104542. doi: 10.15252/embj.2020104542. Epub 2020 Dec 2.
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.
最佳的 DNA 损伤反应与组蛋白的 ADP-核糖基化有关。然而，DNA 损伤诱导的组蛋白 ADP-核糖基化的潜在分子机制仍不清楚。在此，我们使用无偏质谱法鉴定到，在氧化 DNA 损伤后，变体组蛋白 H2AX 的谷氨酸残基 141（E141）被 ADP-核糖基化。通过对野生型 H2AX 和 ADP-核糖基化缺陷型 E141A 突变体进行深入研究，表明 H2AX 的 ADP-核糖基化在碱基切除修复（BER）中发挥关键作用。在机制上，E141 上的 ADP-核糖基化介导 Neil3 糖苷酶在 DNA 损伤部位的募集，以进行 BER。此外，这种 ADP-核糖基化的缺失会增强氧化 DNA 损伤后 H2AX 的丝氨酸 139 磷酸化（γH2AX），并错误地导致 DNA 双链断裂（DSB）反应因子的积累。总之，这些结果表明 H2AX 的 ADP-核糖基化不仅促进了 BER 修复，还抑制了 γH2AX 介导的 DSB 反应。
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