SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

• DOI: 10.1016/j.molcel.2023.02.004
• Publication Date: 2023-02-27T15:35:24Z
• Authors: Jinzhou Huang; Chenming Wu; Jake A. Kloeber; Huanyao Gao; Ming Gao; Qian Zhu; Yiming Chang; Fei Zhao; Guijie Guo; Kuntian Luo; Haiming Dai; Sijia Liu; Qiru Huang; Wootae Kim; Qin Zhou; Shouhai Zhu; Zheming Wu; Xinyi Tu; Ping Yin; Min Deng; Liewei Wang; Jian Yuan; Zhenkun Lou
• Keywords: Mammals; 0303 health sciences; 03 medical and health sciences; DNA End-Joining Repair; DNA Repair; Telomere-Binding Proteins; Animals; DNA Breaks, Double-Stranded; Cell Cycle Proteins; Tumor Suppressor p53-Binding Protein 1; Chromatin

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.