Kalocsay Marian, Hiller Natalie Jasmin, Jentsch Stefan
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Mol Cell. 2009 Feb 13;33(3):335-43. doi: 10.1016/j.molcel.2009.01.016.
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.
DNA双链断裂（DSB）对细胞具有急性危害，因为它们会导致基因组不稳定。DSB修复涉及修复因子依次募集到DSB处，随后是Rad51介导的同源性探测、DNA合成和连接。然而，对于如果未找到同源性且DSB持续存在时细胞如何反应，人们知之甚少。在这里，通过监测单个持续存在的DNA断裂，我们发现，在DNA切除和RPA募集之后，Rad51从DSB双向全染色体扩散，但仅选择性地在断裂的染色体上扩散。值得注意的是，持续存在的DSB随后在一个需要Rad51、组蛋白变体H2A.Z、其SUMO修饰和DNA损伤检查点的过程中固定在核周边。实际上，H2A.Z在断裂处附近早期但短暂地沉积，并指导DNA切除、单个DSB诱导的检查点激活和DSB锚定。因此，一个持续存在的DSB会引发多方面的反应，这与一种特定的染色质标记有关。
