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--蛋白质如何产生和降解--以及稳态--如何保护蛋白质并从功能失调状态(如变性)中恢复，找到一种预测和控制辐射敏感性的新方法。我们获得了以下主要结果。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XRCC4染色质结合所需的蛋白质，并明确了XRCC4的结合区。第三，我们创造了一系列XRCC4和XLF的突变体。在XRCC4中，我们发现除了潜在的磷酸化位点突变外，还有几个突变具有较高的辐射敏感性，这表明可能参与了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了一种新的策略。

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.