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.

转录应激与 DNA 损伤驱动的衰老有关，但其潜在机制仍不清楚。在这里，我们证明Tcea1 ^−/−细胞在转录延伸中存在 TFIIS 缺陷，表现出 RNAPII 在氧化 DNA 损伤位点停滞、转录受损、R 环积累、端粒脱帽、染色质桥和基因组不稳定，最终导致在细胞衰老过程中。我们发现端粒上的 R 环因果关系导致Tcea1 ^-/-细胞和源自自然衰老动物的原代细胞的细胞质中端粒 DNA 片段的释放，从而触发病毒样免疫反应。 TFIIS缺陷细胞释放出载有端粒DNA片段的细胞外囊泡，这些片段以邻近细胞为目标，从而导致细胞衰老。因此，转录应激会引发旁分泌信号，导致细胞衰老，从而促进衰老。