Strategy for the prediction and control of radiosensitivity based on the life-cycle and homeostasis of the DNA repair system

本研究旨在通过分析参与DNA双链断裂修复的蛋白质的生命周期（蛋白质的产生和降解）和稳态（蛋白质的保护和从功能障碍状态（如变性）中恢复），寻找一种预测和控制辐射敏感性的新方法。首先，我们在DNA连接酶IV中发现了染色质结合和稳定的区域。其次，我们发现了XRCC 4与染色质结合所需的蛋白质，并阐明了XRCC 4的结合区域。第三，我们创建了一系列XRCC 4和XLF的突变体。在XRCC 4中，我们发现了几种突变体，而不是潜在的磷酸化位点突变体，具有升高的放射敏感性，这表明可能涉及翻译后修饰而不是磷酸化或蛋白质-蛋白质相互作用。这些结果可能为靶向蛋白质-蛋白质或蛋白质-染色质相互作用的放射增敏提供新的策略。

This study aimed to find a new approach to the prediction and control of radiosensitivity through the analyses of the life cycle-how proteins are generated and degraded - and homeostasis-how proteins are protected and recovered from dysfunctional status, such as denaturation - of proteins involved in DNA double-strand break repair through non-homologous end joining.We obtained the following major outcomes. First, we found regions in DNA ligase IV for chromatin binding and stabilization. Second, we found a protein required for the chromatin binding of XRCC4 and also clarified binding region in XRCC4. Third, we created a series of mutants of XRCC4 and XLF. In XRCC4, we found several mutants, other than potential phosphorylation site mutants, with elevated radiosensitivity, suggesting possible involvement of posttranslational modifications other than phosphorylation or protein-protein interaction. These results might show a new strategy for radiosensitization by targeting the protein-protein or protein-chromatin interactions.