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53BP1 regulates heterochromatin through liquid phase separation

Author

Listed:
  • Lei Zhang

    (Case Western Reserve University, School of Medicine
    Hubei University of Technology)

  • Xinran Geng

    (Case Western Reserve University, School of Medicine)

  • Fangfang Wang

    (Jinan University)

  • Jinshan Tang

    (Jinan University)

  • Yu Ichida

    (Case Western Reserve University, School of Medicine)

  • Arishya Sharma

    (Case Western Reserve University, School of Medicine)

  • Sora Jin

    (Case Western Reserve University, School of Medicine)

  • Mingyue Chen

    (Hubei University of Technology)

  • Mingliang Tang

    (Wuhan University)

  • Franklin Mayca Pozo

    (Case Western Reserve University, School of Medicine)

  • Wenxiu Wang

    (Hubei University of Technology)

  • Janet Wang

    (Case Western Reserve University, School of Medicine)

  • Michal Wozniak

    (Wright State University
    Medical University of Lodz)

  • Xiaoxia Guo

    (Hubei University of Technology)

  • Masaru Miyagi

    (Case Western Reserve University, School of Medicine)

  • Fulai Jin

    (Case Western Reserve University, School of Medicine)

  • Yongjie Xu

    (Wright State University)

  • Xinsheng Yao

    (Jinan University)

  • Youwei Zhang

    (Case Western Reserve University, School of Medicine)

Abstract

Human 53BP1 is primarily known as a key player in regulating DNA double strand break (DSB) repair choice; however, its involvement in other biological process is less well understood. Here, we report a previously uncharacterized function of 53BP1 at heterochromatin, where it undergoes liquid-liquid phase separation (LLPS) with the heterochromatin protein HP1α in a mutually dependent manner. Deletion of 53BP1 results in a reduction in heterochromatin centers and the de-repression of heterochromatic tandem repetitive DNA. We identify domains and residues of 53BP1 required for its LLPS, which overlap with, but are distinct from, those involved in DSB repair. Further, 53BP1 mutants deficient in DSB repair, but proficient in LLPS, rescue heterochromatin de-repression and protect cells from stress-induced DNA damage and senescence. Our study suggests that in addition to DSB repair modulation, 53BP1 contributes to the maintenance of heterochromatin integrity and genome stability through LLPS.

Suggested Citation

  • Lei Zhang & Xinran Geng & Fangfang Wang & Jinshan Tang & Yu Ichida & Arishya Sharma & Sora Jin & Mingyue Chen & Mingliang Tang & Franklin Mayca Pozo & Wenxiu Wang & Janet Wang & Michal Wozniak & Xiaox, 2022. "53BP1 regulates heterochromatin through liquid phase separation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28019-y
    DOI: 10.1038/s41467-022-28019-y
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    Cited by:

    1. Dongmei Wang & Tao Sun & Yuan Xia & Zhe Zhao & Xue Sheng & Shuying Li & Yuechan Ma & Mingying Li & Xiuhua Su & Fan Zhang & Peng Li & Daoxin Ma & Jingjing Ye & Fei Lu & Chunyan Ji, 2023. "Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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