The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.
The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.
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DOI：
10.1016/j.celrep.2018.04.046
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发表时间：
2018-05-15
期刊：
影响因子：
8.8
通讯作者：
Rottenberg S
中科院分区：
文献类型：
--
作者：
Barazas M;Annunziato S;Pettitt SJ;de Krijger I;Ghezraoui H;Roobol SJ;Lutz C;Frankum J;Song FF;Brough R;Evers B;Gogola E;Bhin J;van de Ven M;van Gent DC;Jacobs JJL;Chapman R;Lord CJ;Jonkers J;Rottenberg S
通过聚（ADP-核糖）聚合酶（PARP）抑制剂选择性消除 BRCA1 缺陷细胞是癌症治疗中合成致死概念的一个典型例子。这种相互作用会因 53BP1、RIF1 和 REV7/MAD2L2 等因子的丢失而恢复不依赖于 BRCA1 的同源重组而被抵消，这些因子会抑制 DNA 双链断裂 (DSB) 的末端切除。为了确定参与此过程的其他因素，我们进行了基于 CRISPR/SpCas9 的功能丧失筛选，并选择了在 BRCA1 缺陷细胞中赋予 PARP 抑制剂 (PARPi) 抗性的因素。研究发现，CTC1-STN1-TEN1 (CST) 复合体成员的丢失会导致 BRCA1 缺陷细胞在体外和体内产生 PARPi 耐药性。我们表明，CTC1 耗尽会导致末端切除的恢复，并且 CST 复合物可能在 53BP1/RIF1 下游发挥作用。这些数据表明，除了保护端粒的作用外，CST 复合物还有助于保护 DSB 免遭末端切除。 PARP 抑制剂抗性筛选独立地将 CTC1 的丢失识别为主要打击 CST 复合物促进 BRCA1 缺陷细胞中的 PARP 抑制剂敏感性 CTC1 的耗尽恢复了 BRCA1 缺陷细胞的末端切除 CTC1 通过规范的非同源末端连接促进双链断裂修复 使用基于 CRISPR/SpCas9 的功能丧失筛选，Barazas 等人。研究表明，CTC1-STN1-TEN1 (CST) 复合物的缺失会促进 BRCA1 缺陷细胞对 PARP 抑制剂的耐药性。从机制上讲，CST 复合物除了具有保护端粒末端的作用外，还保持双链断裂末端的稳定性。
Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1-independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells. Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause PARPi resistance in BRCA1-deficient cells in vitro and in vivo. We show that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. These data suggest that, in addition to its role in protecting telomeres, the CST complex also contributes to protecting DSBs from end resection. PARP inhibitor resistance screens independently identify loss of CTC1 as major hit The CST complex promotes PARP inhibitor sensitivity in BRCA1-deficient cells Depletion of CTC1 restores end resection in BRCA1-deficient cells CTC1 facilitates double-strand break repair via canonical non-homologous end joining Using CRISPR/SpCas9-based loss-of-function screens, Barazas et al. show that loss of the CTC1-STN1-TEN1 (CST) complex promotes PARP inhibitor resistance in BRCA1-deficient cells. Mechanistically, the CST complex maintains double-strand break end stability in addition to its role in protecting telomeric ends.
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