The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels

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Chromosomal instability (CIN) in cancer cells has been reported to activate the cGAS-STING innate immunity pathway via micronuclei formation, thus affecting tumor immunity and tumor progression. However, adverse effects of the cGAS/STING pathway as they relate to CIN have not yet been investigated. We addressed this issue using knockdown and add-back approaches to analyze each component of the cGAS/STING/TBK1/IRF3 pathway, and we monitored the extent of CIN by measuring micronuclei formation after release from nocodazole-induced mitotic arrest. Interestingly, knockdown of cGAS (cyclic GMP-AMP synthase) along with induction of mitotic arrest in HeLa and U2OS cancer cells clearly resulted in increased micronuclei formation and chromosome missegregation. Knockdown of STING (stimulator of interferon genes), TBK1 (TANK-binding kinase-1), or IRF3 (interferon regulatory factor-3) also resulted in increased micronuclei formation. Moreover, transfection with cGAMP, the product of cGAS enzymatic activity, as well as add-back of cGAS WT (but not catalytic-dead mutant cGAS), or WT or constitutively active STING (but not an inactive STING mutant) rescued the micronuclei phenotype, demonstrating that all components of the cGAS/STING/TBK1/IRF3 pathway play a role in preventing CIN. Moreover, p21 levels were decreased in cGAS-, STING-, TBK1-, and IRF3-knockdown cells, which was accompanied by the precocious G2/M transition of cells and the enhanced micronuclei phenotype. Overexpression of p21 or inhibition of CDK1 in cGAS-depleted cells reduced micronuclei formation and abrogated the precocious G2/M transition, indicating that the decrease in p21 and the subsequent precocious G2/M transition is the main mechanism underlying the induction of CIN through disruption of cGAS/STING signaling. Cancer: Keeping chromosomes stable during cell division Signaling through cGAS, a protein that detects DNA in the cytosol, prevents chromosome instability (CIN) in cancer cells by regulating the levels of the cell-cycle inhibitor p21. Alterations in chromosome number or structure are hallmarks of cancer cells, but their contribution to disease is unclear. Previous studies have shown that CIN activates cGAS, triggering the activation of an immune response and cell death. However, Jae-Ho Lee at Ajou University, Suwon, South Korea and colleagues now show that defects in cGAS signaling in cells treated with a drug that stops cell-cycle progression leads to CIN and the formation of extra-nuclear bodies containing damaged chromosome fragments, known as micronuclei. Restoring cGAS activity or increasing p21 expression levels prevented micronuclei formation, highlighting a mechanism through which cancer cells can maintain chromosomal stability.
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