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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Unrepaired clustered DNA lesions induce chromosome breakage in human cells
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Unrepaired clustered DNA lesions induce chromosome breakage in human cells

机译：未修复的簇状DNA损伤诱导人类细胞染色体断裂

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摘要

Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling, that the kinetics of loss of clustered DNA lesions was substantially compromised in human fibroblasts. The unique spatial distribution of different types of DNA lesions within the clustered damages, but not the physical location of these damages within the subnuclear domains, determined the cellular ability to repair the damage. We then examined checkpoint arrest mechanisms and yield of gross chromosomal aberrations. Induction of nonrepairable clustered damage affected only G2 accumulation but not the early G2/M checkpoint. Further, cells that were released from the G2/M checkpoint with unrepaired clustered damage manifested a spectrum of chromosome aberrations in mitosis. Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis.
机译：电离辐射诱导的簇状DNA损伤难以修复，并且可能由于未知原因触发致癌事件。在这里，我们使用原位方法直接监测单个细胞中簇状DNA损伤的诱导和修复。我们证明，与生物物理模型一致，在人类成纤维细胞中，簇状DNA损伤的丧失动力学受到了显着损害。簇状损伤内不同类型DNA损伤的独特空间分布，而不是亚损伤域内这些损伤的物理位置，决定了细胞修复损伤的能力。然后，我们检查了检查点停滞机制和总染色体畸变的产生。诱导不可修复的簇状损伤仅影响G2积累，但不影响早期的G2 / M检查点。此外，从G2 / M检查点释放的细胞未经修复的簇状损伤表现出有丝分裂中的染色体畸变谱。在完成簇状DNA损伤修复之前，与簇状DNA损伤修复和检查点释放相关的困难似乎促进了基因组不稳定，可能导致癌变。

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