AI Article Synopsis
- cGAS is a crucial cytosolic DNA sensor that triggers inflammatory responses during cellular senescence, specifically promoting the SASP (senescence-associated secretory phenotype).
- The study identifies that the TOP1cc complex is necessary for cGAS to recognize cytoplasmic chromatin and enhance its function in senescent cells.
- The interaction between TOP1cc and the chromatin protein HMGB2 is vital for this process, influencing how senescent cells respond to immune checkpoint blockade therapies.
Article 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.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031389 | PMC |
| http://dx.doi.org/10.1038/s41467-020-14652-y | DOI Listing |
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