Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 19, 2020
- Source ID
- 10.1038/s41467-020-14652-y
Entities
People
- Bo Zhao
- David W. Speicher
- Hsin-Yao Tang
- Jianhuang Lin
- Katherine M Aird
- Nail Fatkhutdinov
- Pingyu Liu
- Qin Liu
- Rugang Zhang
- Shuai Wu
- Takeshi Fukumoto
- Timothy Nacarelli
Organizations
- Congressionally Directed Medical Research Programs
- Honorable Tina Brozman Foundation
- National Cancer Institute
- National Institute on Aging
- United States Department of Health and Human Services