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Identifier

000463807

Title

The impact of DNA damage on transcriptional stress in mammals

Alternative Title

Η επίπτωση της γενωμικής αστάθειας στη διαδικασία της μεταγραφής στα θηλαστικά

Author

Σιαμέτης, Αθανάσιος Π.

Thesis advisor

Γαρίνης, Γεώργιος

Reviewer

Σπηλιανάκης, Χαράλαμπος
Τζαμαρίας, Δημήτρης
Δελιδάκης, Χρήστος
Ταλιανίδης, Ιωάννης
Μπαζοπούλου, Δάφνη
Κεκλίκογλου, Ιωάννα

Abstract

Transcription stress poses a significant threat to cellular function and genome stability, yet the underlying mechanisms remain unclear. Here, we demonstrate that Tcea1^-/- cells, which harbor a TFIIS defect in transcription elongation, exhibit RNA polymerase II (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 find that R-loops on telomeres causally contribute to the release of telomeric DNA fragments in the cytoplasm of Tcea1-/- cells and naturally aged animal-derived primary cells triggering a viral-like immune response. Importantly, we uncover a novel mechanism wherein TFIIS defective cells release extracellular vesicles laden with telomeric DNA fragments, effectively targeting neighboring cells and inducing bystander senescence. Together, these findings unravel the functional interplay between transcription stress, immune activation, and paracrine cellular senescence with important ramifications for natural aging and the premature onset of age-related diseases.

Language

English

Subject

Genome instability

Telomeres

Transcription

Γενετικές βλάβες

Τελομερή

Issue date

2024-07-26

Collection

School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses