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DNA双链断裂修复中蛋白质的生命周期（蛋白质是如何产生和降解的）和稳态（蛋白质是如何从功能失调状态（如变性）中得到保护和恢复的），找到一种预测和控制辐射敏感性的新方法。取得了以下主要成果。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，并明确了XRCC4的结合区域。第三，我们创建了一系列XRCC4和XLF突变体。在XRCC4中，我们发现除了潜在的磷酸化位点突变体外，还有几个突变体具有更高的放射敏感性，这表明除了磷酸化或蛋白质相互作用之外，可能还涉及翻译后修饰。这些结果可能显示了一种新的靶向蛋白质或蛋白质-染色质相互作用的放射致敏策略。

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.