Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number908
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zhao, B., Liu, P., Fukumoto, T., Nacarelli, T., Fatkhutdinov, N., Wu, S., Lin, J., Aird, K. M., Tang, H. Y., Liu, Q., Speicher, D. W., & Zhang, R. (2020). Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence. Nature communications, 11(1), [908]. https://doi.org/10.1038/s41467-020-14652-y