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 and Rugang Zhang ()
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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
Rugang Zhang: The Wistar Institute

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14652-y

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