Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation.

Cinat, D.; van der Wal, R.; Baanstra, M.; Gamez, A. A. S.; Jellema-de Bruin, A.; van Goethem, M.-J.; van Vugt, M.; Barazzuol, L.; Coppes, R. P.

doi:10.1101/2024.02.14.580306

bioRxiv · 10.1101/2024.02.14.580306

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation.

Cinat, D.·van der Wal, R.·Baanstra, M.·Gamez, A. A. S.·Jellema-de Bruin, A.·van Goethem, M.-J.·van Vugt, M.·Barazzuol, L.·Coppes, R. P.

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Abstract

Radiotherapy is a mainstay in cancer treatment, aiming to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues. However, the collateral damage to normal tissues, especially stem/progenitor cells essential for tissue regeneration and organ function, remains a significant challenge. Here, we investigate the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment, using organoids. Multiomics analysis reveals a stronger double-stranded RNA (dsRNA)-induced type I interferon (IFN-I) response following proton irradiation, driven by loss of heterochromatin regulators and derepression of transposable elements (TEs). This response, mediated by the cytoplasmic sensor RIG-I, enhances the inflammatory signaling initiated by the canonical dsDNA sensors cGAS and ZBP1. Genetic and pharmacological modulation of IFN-I signaling in vitro and in vivo demonstrates its critical role in enhancing stem/progenitor cell activity post-irradiation. Our findings reveal a pro-regenerative role of TE derepression-mediated IFN-I response suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects. TeaserTransposable element-mediated type I interferon signaling enhances stem/progenitor cell activity after irradiation.

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Cinat, D., van der Wal, R., Baanstra, M., Gamez, A. A. S., Jellema-de Bruin, A., van Goethem, M.-J., van Vugt, M., Barazzuol, L., Coppes, R. P.. 2024-02-15. Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation.. https://doi.org/10.1101/2024.02.14.580306

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