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| Item Type: | Preprint |
|---|---|
| Title: | STING safeguards epithelial genome integrity and protects from carcinogenesis via mitotic checkpoint control |
| Creators Name: | Xiang, Hang, Macino, Martina, Woitaske-Proske, Clemens, Bodenstein, Nicholas, Bernardes, Joana P, Schmid, Nicole A., Martini, Gabriela Rios, Wotawa, Felix, Bornhaeuser, Johanna, Kakavand, Nassim, Dyck Dionisi, Oliver, Bossche, Silke van den, Yang, Guang, Wu, Qicong, Kugler, Julia, Welz, Lina, Konukiewitz, Bjorn, Fischer, Julius C., Peifer, Christian, Rad, Roland, Schreiber, Stefan, Rosenstiel, Philip, Tschurtschenthaler, Markus, Sanders, Ashley D. and Aden, Konrad |
| Abstract: | The cGAS-STING pathway is a central regulator of anti-tumor immunity, sensing cytosolic double-stranded DNA and inducing type I interferon responses. However, whether cGAS-STING directly coordinates DNA damage response in non-immune cells and thereby contributes to cell-intrinsic prevention of oncogenesis is not known. Using mouse models with deletion of ribonucleotide excision repair in the intestinal epithelium (H2b(ΔIEC)) and additional knock-out of STING (H2b(ΔIEC)/STING(-/-), H2b/STING(ΔIEC)) we show that STING deficiency compromises DNA damage induced signalling via ATM and impairs homologous recombination repair, thereby promoting chromosomal instability and driving formation of spontaneous intestinal adenocarcinoma. Mechanistically, STING loss disrupts the NBS1-ATM axis and attenuates DNA damage signalling through enhanced phosphatase-mediated signal termination. Using single strand sequencing, we show that epithelial loss of STING promotes chromosomal instability and accumulation of mutations. By employing kinase screening, we further show that STING deficiency abrogates p53-dependent checkpoint control via overactivation of Cyclin-dependent kinase 1 (CDK1). CDK1 inhibitors lead to a STING-specific sensitization of tumor organoids and colorectal cancer cell lines, pointing towards a STING-specific vulnerability of tumors to CDK1 inhibition. Together, these data identify STING as an epithelial, interferon-independent genome-integrity checkpoint that couples DNA damage signaling to cell-cycle control, thereby restraining chromosomal instability, tumor evolution and revealing a therapeutically exploitable vulnerability in colorectal cancer. |
| Keywords: | STING, p53, ATM, RNase H2b, Colorectal Cancer, DNA Damage, Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.02.17.706442 |
| Date: | 18 February 2026 |
| Official Publication: | https://doi.org/10.64898/2026.02.17.706442 |
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