Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Mol Cell. 2023 Apr 6;83(7):1043-1060.e10. doi: 10.1016/j.molcel.2023.02.004. Epub 2023 Feb 27.
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.
DNA 双链断裂 (DSBs) 的修复会引发三维 (3D) 染色质拓扑变化。最近的一项发现表明，53BP1 会在 DSB 周围组装成一种 3D 染色质拓扑模式。这种高级结构的形成方式和调控机制仍然很神秘。在这里，我们报告 SLFN5 是 DSB 处 53BP1 拓扑排列的关键因素。通过超分辨率成像，我们发现 SLFN5 结合到 53BP1 染色质域上，通过驱动 DSB 和去保护端粒处的受损染色质动力学，组装出更高阶的微区结构。从机制上讲，我们提出 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流动性，以及 (2)由 SLFN5 介导的 53BP1 寡聚物的组装。在哺乳动物中，SLFN5 的缺乏会破坏 DSB 修复拓扑结构，并损害非同源末端连接、端粒融合、类别转换重组以及对聚 (ADP-核糖) 聚合酶抑制剂的敏感性。我们建立了一种分子机制，这种机制可以塑造高阶染色质拓扑结构，以维护基因组稳定性。
