This mechanism may be modulated through senescent-inducing chemotherapy to prevent cancer cells from proliferating.
Cellular senescence is a natural tumor-suppressing process that permanently inhibits the spread of damaged or premalignant cells.
CGMP-AMP synthase (cGAS) senses cytosolic DNA and stimulates senescence and immunity by activating a series of cellular events resulting in the development of inflammatory molecules collectively known as senescence-associated secretory phenotype (SASP).
To analyze this, the Zhang lab based on proteins attached to cytoplasmic DNA in senescent cells and identified topoisomerase 1 (TOP1), an enzyme that unwinds the DNA helix to allow its replication and transcription of RNA as a missing link between cGAS and DNA.
TOP1 interacts with cytosolic DNA and cGAS, connecting the two and promoting the DNA-sensing function of cGAS.
3 KEY POINTS:
1. Cells that have been subject to multiple stressors and have undergone substantial damage to DNA, for example, through chemotherapy, carry DNA fragments from the nucleus to the cytoplasm as a way of signaling that something is wrong.
2. A novel molecular pathway involved in the immunotherapy response was identified, considering it as an essential step in mediating the senescence reaction and activating SASP.
3. TOP1 inhibitors have potential uses to sensitize tumors to immunotherapy, particularly for cancer cells that become senescent in response to therapies such as chemotherapy or radiotherapy.
“We suggest that this pathway might be targeted to modulate senescence-inducing effects of cancer therapeutics and affect the response of senescent cancer cells to immunotherapy.” said lead researcher Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center.
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