Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites.
Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites.
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DOI：
10.1016/j.celrep.2015.03.058
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发表时间：
2015-05-05
期刊：
影响因子：
8.8
通讯作者：
Jackson SP
中科院分区：
文献类型：
--
作者：
Brown JS;Lukashchuk N;Sczaniecka-Clift M;Britton S;le Sage C;Calsou P;Beli P;Galanty Y;Jackson SP
许多DNA修复蛋白的活性通过泛素和泛素样分子的可逆共价修饰来控制。非同源末端连接（NHEJ）是哺乳动物细胞中主要的DNA双链断裂（DSB）修复途径，由Ku 70/Ku 80（Ku）异源二聚体识别DSB末端启动。通过在临床试验中使用MLN 4924（一种特异性抑制泛素样蛋白NEDD 8与靶蛋白结合的抗癌药物），我们证明了NEDD 8在DNA损伤位点的蓄积是一个高度动态的过程。此外，我们表明，耗尽细胞的NEDD 8 E2-共轭酶，UBE 2 M，产生电离辐射超敏反应和减少细胞存活NHEJ后。最后，我们证明了neddylation促进Ku泛素化DNA损伤后和Ku和Ku相关蛋白从损伤部位修复后释放。这些研究提供了NHEJ核心复合物如何从修复位点解离的见解，并强调了其在DSB诱导后对细胞存活的重要性。NEDD 8在DNA损伤位点的积累是一个动态过程NEDD 8 E2 UBE 2 M的消耗降低了NHEJ后的细胞存活Neddylation促进DNA损伤后Ku的泛素化Neddylation促进DNA修复后Ku从损伤位点释放双链断裂（DSB）修复对基因组稳定性至关重要，并受到泛素和泛素样分子修饰蛋白质的严格调控。Brown等人显示，在修复完成后，neddylation促进从受损DNA释放主要DSB传感器Ku，提供了对长期寻求的机制的深入了解。
The activities of many DNA-repair proteins are controlled through reversible covalent modification by ubiquitin and ubiquitin-like molecules. Nonhomologous end-joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in mammalian cells and is initiated by DSB ends being recognized by the Ku70/Ku80 (Ku) heterodimer. By using MLN4924, an anti-cancer drug in clinical trials that specifically inhibits conjugation of the ubiquitin-like protein, NEDD8, to target proteins, we demonstrate that NEDD8 accumulation at DNA-damage sites is a highly dynamic process. In addition, we show that depleting cells of the NEDD8 E2-conjugating enzyme, UBE2M, yields ionizing radiation hypersensitivity and reduced cell survival following NHEJ. Finally, we demonstrate that neddylation promotes Ku ubiquitylation after DNA damage and release of Ku and Ku-associated proteins from damage sites following repair. These studies provide insights into how the NHEJ core complex dissociates from repair sites and highlight its importance for cell survival following DSB induction. NEDD8 accumulation at DNA-damage sites is a dynamic process Depletion of the NEDD8 E2 UBE2M reduces cell survival following NHEJ Neddylation promotes ubiquitylation of Ku following DNA damage Neddylation promotes Ku release from damage sites following DNA repair Double-strand break (DSB) repair is essential for genomic stability and is tightly regulated by modification of proteins with ubiquitin and ubiquitin-like molecules. Brown et al. show that, upon completion of repair, neddylation promotes release of the main DSB sensor Ku from damaged DNA, providing insight into a long-sought mechanism.
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