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Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence

Author

Listed:
  • Bo Zhao

    (The Wistar Institute)

  • Pingyu Liu

    (The Wistar Institute)

  • Takeshi Fukumoto

    (The Wistar Institute)

  • Timothy Nacarelli

    (The Wistar Institute)

  • Nail Fatkhutdinov

    (The Wistar Institute)

  • Shuai Wu

    (The Wistar Institute)

  • Jianhuang Lin

    (The Wistar Institute)

  • Katherine M. Aird

    (The Wistar Institute)

  • Hsin-Yao Tang

    (The Wistar Institute)

  • Qin Liu

    (The Wistar Institute)

  • David W. Speicher

    (The Wistar Institute
    The Wistar Institute)

  • Rugang Zhang

    (The Wistar Institute)

Abstract

Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade.

Suggested Citation

  • Bo Zhao & Pingyu Liu & Takeshi Fukumoto & Timothy Nacarelli & Nail Fatkhutdinov & Shuai Wu & Jianhuang Lin & Katherine M. Aird & Hsin-Yao Tang & Qin Liu & David W. Speicher & Rugang Zhang, 2020. "Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14652-y
    DOI: 10.1038/s41467-020-14652-y
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