PDF(Pubmed)
Abstract：
Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.
摘要：
DNA双链断裂（DSB）的修复引起三维（3D）染色质拓扑变化。最近的发现表明，53BP1在DSB周围组装成3D染色质拓扑模式。如何配置和调节这种高阶结构的形成仍然是一个谜。这里,我们报告说，SLFN5是DSB上53BP1拓扑排列的关键因素。使用超分辨率成像，我们发现，SLFN5结合53BP1染色质结构域，通过驱动DSB和去保护端粒上受损的染色质动力学来组装高阶微域结构。机械上,我们认为53BP1拓扑结构由两个过程形成：（1）由SLFN5-LINC微管轴驱动的染色质迁移率和（2）由SLFN5介导的53BP1寡聚体的组装。在哺乳动物中,SLFN5缺陷破坏DSB修复拓扑结构并损害非同源末端连接，端粒融合,类开关重组，和对聚(ADP-核糖)聚合酶抑制剂的敏感性。我们建立了一种形成高阶染色质拓扑结构的分子机制，以保护基因组的稳定性。
