Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for cellular senescence and immune responses.
• cGAS triggers the senescence-associated secretory phenotype (SASP) by sensing cytoplasmic chromatin.
• The precise mechanism of cGAS-mediated cytoplasmic chromatin recognition remains elusive.

Purpose of the Study:

• To elucidate the mechanism by which cGAS recognizes cytoplasmic chromatin during senescence.
• To identify key factors involved in cGAS-mediated SASP induction.
• To understand the role of this pathway in anti-tumor immunity.

Main Methods:

• Investigated the interaction between cGAS, chromatin, and associated proteins.
• Utilized techniques to visualize and quantify TOP1cc localization in the cytoplasm.
• Assessed the functional impact of the HMGB2-TOP1cc-cGAS axis on SASP and immune responses in vivo.

Main Results:

• Topoisomerase 1-DNA covalent complexes (TOP1cc) are necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP.
• TOP1cc localizes to cytoplasmic chromatin and interacts with cGAS, enhancing DNA binding.
• HMGB2 stabilizes TOP1cc on cytoplasmic chromatin, forming a critical HMGB2-TOP1cc-cGAS axis.
• This axis dictates the response of senescent cells to immune checkpoint blockade in vivo.

Conclusions:

• Established a novel HMGB2-TOP1cc-cGAS axis essential for cytoplasmic chromatin recognition during senescence.
• This pathway is a key determinant of the senescence-associated secretory phenotype.
• The HMGB2-TOP1cc-cGAS axis plays a critical role in mediating the anti-tumor effects of immune checkpoint blockade.