Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence

Nat Commun. 2020 Feb 19;11(1):908. doi: 10.1038/s41467-020-14652-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology
  • Cell Line
  • Cellular Senescence / immunology*
  • Chromatin / immunology
  • Chromatin / metabolism
  • Cytosol / immunology
  • Cytosol / metabolism
  • DNA / immunology
  • DNA / metabolism
  • DNA Damage / immunology
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism*
  • Gene Knockdown Techniques
  • HMGB2 Protein / genetics
  • HMGB2 Protein / metabolism*
  • Humans
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neoplasms / immunology
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Protein Binding
  • Xenograft Model Antitumor Assays


  • B7-H1 Antigen
  • Chromatin
  • HMGB2 Protein
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human
  • DNA Topoisomerases, Type I
  • TOP1 protein, human