DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.
DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.
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DOI：
10.1016/j.cell.2018.03.050
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发表时间：
2018-05-03
期刊：
影响因子：
64.5
通讯作者：
Choudhary C
中科院分区：
文献类型：
--
作者：
Gupta R;Somyajit K;Narita T;Maskey E;Stanlie A;Kremer M;Typas D;Lammers M;Mailand N;Nussenzweig A;Lukas J;Choudhary C
受损DNA的修复对于维持基因组完整性和预防基因组不稳定性相关疾病（如癌症）至关重要。通过将邻近标记与定量质谱相结合，我们生成了内源性表达的DNA修复因子53 BP 1、BRCA 1和MDC 1的高分辨率相互作用邻域图。我们的空间分辨相互作用图揭示了丰富的网络复杂性，识别共享和诱饵特异性相互作用模块，并在此过程中牵连以前隐藏的监管机构。我们鉴定了一种新的脊椎动物特异性蛋白复合物shieldin，其包含REV 7加上三种先前未表征的蛋白质RINN 1（CTC-534A2.2）、RINN 2（FAM 35 A）和RINN 3（C20 ORF 196）。通过ATM-RNF 8-RNF 168 - 53 BP 1-RIF 1轴将shieldin募集到DSB，促进NHEJ依赖的染色体内断裂修复、免疫球蛋白类别转换重组（CSR）和未受保护的端粒融合。Shieldin作为53 BP 1-RIF 1的下游效应物，在抑制DNA末端切除和使BRCA 1缺陷细胞对PARP抑制剂敏感中起作用。这些发现对理解癌症相关的PARPi抗性和高等脊椎动物中抗体CSR的进化具有意义。
Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1. Our spatially resolved interaction maps reveal rich network intricacies, identify shared and bait-spe-cific interaction modules, and implicate previously concealed regulators in this process. We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously unchar-acterized proteins, RINN1 (CTC-534A2.2), RINN2 (FAM35A), and RINN3 (C20ORF196). Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168–53BP1-RIF1 axis, promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unpro-tected telomeres. Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resec-tion and in sensitizing BRCA1-deficient cells to PARP inhibitors. These findings have implications for under-standing cancer-associated PARPi resistance and the evolution of antibody CSR in higher vertebrates.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
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影响因子：
64.8
作者：
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de lange, Titia
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由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
Durocher, Daniel