An Inhibitor of Nonhomologous End-Joining Abrogates Double-Strand Break Repair and Impedes Cancer Progression
An Inhibitor of Nonhomologous End-Joining Abrogates Double-Strand Break Repair and Impedes Cancer Progression
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DOI：
10.1016/j.cell.2012.11.054
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发表时间：
2012-12-21
期刊：
影响因子：
64.5
通讯作者：
Raghavan, Sathees C.
中科院分区：
文献类型：
--
作者：
Srivastava, Mrinal;Nambiar, Mridula;Raghavan, Sathees C.
DNA连接酶IV负责在非同源末端连接（NHEJ）期间密封双链断裂（DSB）。抑制连接酶IV可导致DSB的积累，从而用作治疗癌症的策略。在这里，我们确定了一个分子，SCR7，抑制加入DSB在无细胞修复系统。SCR7通过干扰其DNA结合而不是T4 DNA连接酶或连接酶I的DNA结合来阻断连接酶IV介导的连接。SCR7在细胞内以连接酶IV依赖性方式抑制NHEJ，并激活内在凋亡途径。更重要的是，SCR7在小鼠模型中阻碍肿瘤进展，并且当与DSB诱导治疗方式共同施用时，显着增强其敏感性。这种靶向NHEJ的抑制剂提供了一种治疗癌症和改善现有方案的策略。
DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.