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

  • Mol Cell. 2023 Feb 25;S1097-2765(23)00083-7. doi: 10.1016/j.molcel.2023.02.004.
Jinzhou Huang  1 ,  Chenming Wu  2 ,  Jake A Kloeber  3 ,  Huanyao Gao  4 ,  Ming Gao  1 ,  Qian Zhu  1 ,  Yiming Chang  5 ,  Fei Zhao  1 ,  Guijie Guo  1 ,  Kuntian Luo  1 ,  Haiming Dai  1 ,  Sijia Liu  6 ,  Qiru Huang  1 ,  Wootae Kim  1 ,  Qin Zhou  1 ,  Shouhai Zhu  1 ,  Zheming Wu  1 ,  Xinyi Tu  1 ,  Ping Yin  1 ,  Min Deng  1 ,  Liewei Wang  4 ,  Jian Yuan  7 ,  Zhenkun Lou  8
Affiliations
  • 1. Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 2. 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.
  • 3. Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA.
  • 4. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 5. Jinzhou Medical University, Shanghai East Hospital, Shanghai 200120, China.
  • 6. Department of Artificial Intelligence and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
  • 7. 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; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200092, China. Electronic address: [email protected].
  • 8. Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].
PMID: 36854302 DOI: 10.1016/j.molcel.2023.02.004
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.

Keywords
53BP1; DNA double-strand break repair; PARP inhibitor sensitivity; SLFN5; chromatin mobility; chromatin topology; class switch recombination; non-homologous end joining; super-resolution microscopy; telomere fusions.
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