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

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.

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All data generated during this study are included in the published article (and its supplementary information files).The RNA-Seq data (PRJEB63556) are deposited in ArrayExpress (https://www.ebi.ac.uk/arrayexpress/).The Cytoseq data (PRJEB71474) are deposited on the European Nucleotide Archive.Information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, George A. Garinis (garinis@imbb.forth.gr).Original western blot images, microscopy data and all other raw data will be shared by the lead contact upon request.
Sample size calculation was based on 1. effect size (the difference between the mean of two groups), 2. the standard deviation or standard error of the mean variability within the sample, 3. the decision of direction of effect (two tailed for all experiments performed).According to these criteria n was calculated to be the minimum required number of experiments (least possible animals used) to provide the study with reasonable statistical power.
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