Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy
Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy
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DOI：
10.1172/jci92742
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发表时间：
2018-01-02
影响因子：
15.9
通讯作者：
Deng, Xingming
中科院分区：
文献类型：
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作者：
Chen, Guo;Magis, Andrew T.;Deng, Xingming
DNA双链断裂（DSB）主要通过同源重组（HR）或非同源末端连接（NHEJ）途径修复。在这里，我们表明，髓细胞白血病序列1（Mcl-1）作为一个功能开关在HR和NHEJ途径之间的选择。Mcl-1在HR过程中受细胞周期调控，在S/G（2）期表达最高。虽然内源性Mcl-1耗竭降低HR并增强NHEJ，但Mcl-1过表达导致HR相对于NHEJ的净增加。Mcl-1通过其Bcl-2同源1和3（BH 1和BH 3）结构域与二聚Ku蛋白复合物直接相互作用，这是Mcl-1抑制Ku介导的NHEJ所需的。Mcl-1还促进由Mre 11复合物介导的DNA切除和HR依赖性DSB修复。使用Mcl-1 BH 1结构域作为对接位点，我们鉴定了一种小分子MI-223，其直接与BH 1结合并阻断Mcl-1刺激的HR DNA修复，导致癌细胞对羟基脲或奥拉帕尼诱导的DNA复制应激敏感。MI-223和羟基脲或奥拉帕尼的联合治疗在体内表现出对肺癌的强协同作用。这种机制驱动的药物组合提供了一个非常有吸引力的治疗策略，以改善肺癌的结果。
DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G(2) phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ. Mcl-1 also promoted DNA resection mediated by the Mre11 complex and HR-dependent DSB repair. Using the Mcl-1 BH1 domain as a docking site, we identified a small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair, leading to sensitization of cancer cells to hydroxyurea-or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcomes.