Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence

Bo Zhao,Nail Fatkhutdinov,Takeshi Fukumoto,Pingyu Liu,Rugang Zhang,Timothy Nacarelli,Jianhuang Lin,Shuai Wu,Qin Liu,Katherine M Aird,Hsin-Yao Tang,David W Speicher

doi:10.1038/s41467-020-14652-y

Bo Zhao, Nail Fatkhutdinov + Show 10 more

Open Access

https://doi.org/10.1038/s41467-020-14652-y

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Journal: Nature Communications	Publication Date: Feb 19, 2020
Citations: 43	License type: open-access

Affiliation: 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.

Highlights

Cyclic cGMP-AMP synthase 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
Since high-mobility group box 2 (HMGB2) positively regulates SASP15 and facilitates cytosolic nucleic acid sensing[16], we examined whether HMGB2 localized to the cytoplasmic chromatin fragments (CCF) during senescence
The analysis revealed that topoisomerase 1 (TOP1) was among the top differentially proteins in CCF isolated from senescent cells, with or without HMGB2 knockdown

Summary

Introduction

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. CGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. 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. 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. The activation of cGAS in senescent cells is due to the induction of cytoplasmic chromatin fragments (CCF) caused by nuclear membrane blebbing[3,10]. The role of TOP1cc in senescence has never been explored

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