Chromosome-wide Rad51 Spreading and SUMO-H2A.Z-Dependent Chromosome Fixation in Response to a Persistent DNA Double-Strand Break
Chromosome-wide Rad51 Spreading and SUMO-H2A.Z-Dependent Chromosome Fixation in Response to a Persistent DNA Double-Strand Break
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DOI：
10.1016/j.molcel.2009.01.016
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发表时间：
2009-02-13
期刊：
影响因子：
16
通讯作者：
Jentsch, Stefan
中科院分区：
文献类型：
--
作者：
Kalocsay, Marian;Hiller, Natalie Jasmin;Jentsch, Stefan
DNA 双链断裂 (DSB) 对细胞来说非常危险，因为它们会导致基因组不稳定。 DSB 修复涉及将修复因子顺序招募到 DSB，然后是 Rad51 介导的同源性探测、DNA 合成和连接。然而，如果没有发现同源性且 DSB 持续存在，细胞如何反应我们知之甚少。在这里，通过监测单个持续性 DNA 断裂，我们发现，在 DNA 切除和 RPA 招募后，Rad51 从 DSB 双向传播到染色体范围内，但选择性地仅在断裂的染色体上传播。值得注意的是，持久性 DSB 随后被固定到核外围，这一过程需要 Rad51、组蛋白变体 H2A.Z、其 SUMO 修饰和 DNA 损伤检查点。事实上，H2A.Z 早期但短暂地沉积在断裂附近，并指导 DNA 切除、单个 DSB 诱导的检查点激活和 DSB 锚定。因此，持续的 DSB 会诱导多方面的反应，这与特定的染色质标记有关。
DNA double-strand breaks (DSBs) are acutely hazardous for cells, as they can cause genome instability. DSB repair involves the sequential recruitment of repair factors to the DSBs, followed by Rad51 mediated homology probing, DNA synthesis, and ligation. However, little is known about how cells react if no homology is found and DSBs persist. Here, by monitoring a single persistent DNA break, we show that, following DNA resection and RPA recruitment, Rad51 spreads chromosome-wide bidirectionally from the DSB but selectively only on the broken chromosome. Remarkably, the persistent DSB is later fixed to the nuclear periphery in a process that requires Rad51, the histone variant H2A.Z, its SUMO modification, and the DNA-damage checkpoint. Indeed, H2A.Z is deposited close to the break early but transiently and directs DNA resection, single DSB-induced checkpoint activation, and DSB anchoring. Thus, a persistent DSB induces a multifaceted response, which is linked to a specific chromatin mark.