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

Abstract

The release and subsequent detection of nucleic acids into the cytoplasm constitute a hallmark of the radiation-induced DNA damage response. However, different radiation types, such as photons and protons, may elicit distinct DNA damage responses, uniquely influencing normal stem cell activity and tissue regeneration. Here, we show that proton irradiation leads to enhanced derepression of transposable elements (TEs) with consequent activation of salivary gland stem/progenitor cells. This response is mediated by a pronounced loss of heterochromatin regulators and accumulation of cytoplasmic TE-derived dsRNA, resulting in upregulation of RIG-I and augmented interferon-beta (IFN-β) signaling. Single cell RNA sequencing (scRNA-seq) and TE dynamics analyses corroborate these findings, specifically in a subpopulation of Sox9-expressing stem/progenitor cells with increased INF-β response. These data reveal that the presence of TE-derived IFN-β in the microenvironment of irradiated organoids increases stem/progenitor cell activity and organoid growth, pointing to advantages of proton therapy over photon-based radiotherapy.

Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors

“…Increased micronucleus formation following DNA repair inhibition and high-LET irradiation could thus likely result in higher IFN-β levels. Additionally, in a recent study, higher IFN-β signaling after proton than photon irradiation was associated with proton-induced activation of transposable elements, likely due to the aforementioned opening of compacted chromatin [ 131 ]. As non-repaired clustered DNA damage can cause changes in chromatin structure [ 132 ], it is thus tempting to speculate that co-treatment with DNA repair inhibitors and high-LET radiation could result in the further opening of compacted chromatin, and thereby heighten the transcription of retrotransposons or other transposable elements.…”

“…As non-repaired clustered DNA damage can cause changes in chromatin structure [ 132 ], it is thus tempting to speculate that co-treatment with DNA repair inhibitors and high-LET radiation could result in the further opening of compacted chromatin, and thereby heighten the transcription of retrotransposons or other transposable elements. This could likely result in cytosolic dsRNA that stimulates RIG-1-dependent IFN transcription [ 131 ]. Moreover, another potential mechanism that could give an elevated IFN response after treatment with DNA repair inhibitors and high-LET radiation is the leakage of small, radiation-induced DNA fragments from the nucleus into the cytosol [ 107 ].…”