Unrepaired clustered DNA lesions induce chromosome breakage in human cells
Unrepaired clustered DNA lesions induce chromosome breakage in human cells
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DOI：
10.1073/pnas.1016045108
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发表时间：
2011-05-17
影响因子：
11.1
通讯作者：
Chen, David J.
中科院分区：
文献类型：
--
作者：
Asaithamby, Aroumougame;Hu, Burong;Chen, David J.
电离辐射引起的DNA损伤是难以修复的，并可能引发致癌事件，原因尚不清楚。在这里，我们使用原位方法直接监测单个细胞中成簇DNA损伤的诱导和修复。我们发现，与生物物理建模一致，在人成纤维细胞中，成簇DNA损伤的丢失动力学基本上受到损害。不同类型的DNA损伤在簇状损伤内的独特空间分布，而不是这些损伤在亚核结构域内的物理位置，决定了细胞修复损伤的能力。然后，我们检查了检查点阻滞机制和总染色体畸变的产量。诱导不可修复的簇状损伤只影响G2积累，但不影响早期G2/M检查点。此外，从G2/M检查点释放的具有未修复的簇状损伤的细胞在有丝分裂中表现出一系列染色体畸变。与成簇DNA损伤修复和在成簇DNA损伤修复完成之前释放检查点相关的困难似乎促进了可能导致致癌的基因组不稳定性。
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.