2. Academic Validation
  3. SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

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

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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