Nucleosomal histones are barriers to the DNA repair process particularly at DNA double-strand breaks (DSBs). However, the molecular mechanism by which these histone barriers are removed from the sites of DNA damage remains elusive. Here, we have generated a single specific inducible DSB in the cells and systematically examined the histone removal process at the DNA lesion. We found that histone removal occurred immediately following DNA damage and could extend up to a range of few kilobases from the lesion. To examine the molecular mechanism underlying DNA damage-induced histone removal, we screened histone modifications and found that histone ADP-ribosylation was associated with histone removal at DNA lesions. PARP inhibitor treatment suppressed the immediate histone eviction at DNA lesions. Moreover, we examined histone chaperones and found that the FACT complex recognized ADP-ribosylated histones and mediated the removal of histones in response to DNA damage. Taken together, our results reveal a pathway that regulates early histone barrier removal at DNA lesions. It may also explain the mechanism by which PARP inhibitor regulates early DNA damage repair.

中文翻译：

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聚（ADP-核糖基）化介导 DNA 损伤处的早期组蛋白驱逐。

核小体组蛋白是 DNA 修复过程的障碍，特别是在 DNA 双链断裂 (DSB) 处。然而，这些组蛋白屏障从 DNA 损伤部位去除的分子机制仍然难以捉摸。在这里，我们在细胞中生成了一个特定的可诱导 DSB，并系统地检查了 DNA 损伤处的组蛋白去除过程。我们发现组蛋白的去除会在 DNA 损伤后立即发生，并且可以从病变延伸到几千个碱基的范围。为了检查 DNA 损伤诱导组蛋白去除的分子机制，我们筛选了组蛋白修饰，发现组蛋白 ADP 核糖基化与 DNA 损伤处的组蛋白去除有关。PARP 抑制剂治疗抑制了 DNA 损伤处的立即组蛋白驱逐。而且，我们检查了组蛋白伴侣，发现 FACT 复合物识别 ADP 核糖基化组蛋白并介导组蛋白的去除以响应 DNA 损伤。总之，我们的结果揭示了一种调节 DNA 损伤处早期组蛋白屏障去除的途径。它还可以解释 PARP 抑制剂调节早期 DNA 损伤修复的机制。