Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence

Athanasios Siametis, Kalliopi Stratigi, Despoina Giamaki, Georgia Chatzinikolaou, Alexia Akalestou-Clocher, Evi Goulielmaki, Brian Luke, Björn Schumacher and George A. Garinis ()
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Athanasios Siametis: Foundation for Research and Technology-Hellas
Kalliopi Stratigi: Foundation for Research and Technology-Hellas
Despoina Giamaki: Foundation for Research and Technology-Hellas
Georgia Chatzinikolaou: Foundation for Research and Technology-Hellas
Alexia Akalestou-Clocher: Foundation for Research and Technology-Hellas
Evi Goulielmaki: Foundation for Research and Technology-Hellas
Brian Luke: Johannes Gutenberg-Universität
Björn Schumacher: University of Cologne
George A. Garinis: Foundation for Research and Technology-Hellas

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Transcription stress has been linked to DNA damage -driven aging, yet the underlying mechanism remains unclear. Here, we demonstrate that Tcea1−/− cells, which harbor a TFIIS defect in transcription elongation, exhibit RNAPII stalling at oxidative DNA damage sites, impaired transcription, accumulation of R-loops, telomere uncapping, chromatin bridges, and genome instability, ultimately resulting in cellular senescence. We found that R-loops at telomeres causally contribute to the release of telomeric DNA fragments in the cytoplasm of Tcea1−/− cells and primary cells derived from naturally aged animals triggering a viral-like immune response. TFIIS-defective cells release extracellular vesicles laden with telomeric DNA fragments that target neighboring cells, which consequently undergo cellular senescence. Thus, transcription stress elicits paracrine signals leading to cellular senescence, promoting aging.

Date: 2024
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DOI: 10.1038/s41467-024-48443-6

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