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Identifier 000449412
Title TFIIS-mediated telomere dysfunction and cellular senescence
Alternative Title Ο ρόλος της TFIIS πρωτεΐνης στο μεταγραφικό στρες και στην κυτταρική γήρανση
Author Γιαμάκη, Δέσποινα Β.
Thesis advisor Γαρίνης, Γεώργιος
Reviewer Ζάχος, Γεώργιος
Σπηλιανάκης, Χαράλαμπος
Abstract Although it is known that transcription stress can be associated with genome instability, the molecular mechanisms underlying the correlations between them and how these links might affect aging and age-related diseases remain unclear. Transcription stress takes place every time RNA polymerase II is arrested due to physiological or extrinsic stressors, including DNA damage, such as bulky lesions and double strand breaks. To overcome these roadblocks, RNA pol II has an endonuclease activity, stimulated by transcription elongation factor TFIIS, allowing transcription elongation to resume. Here, we used TFIIS-deficient mouse embryonic fibroblasts, aiming to specifically induce transcription stress and investigate the molecular mechanisms underlying the links between DNA damage, repair and transcription in health and disease. In this study, we uncover, for the first time, an interplay between transcription stress and cellular senescence. Indeed, we demonstrate that upon TFIIS depletion, cells accumulate DNA damage and become senescent. Remarkably, we found that the absence of TFIIS induces telomere dysfunction and chromosomal abnormalities, affecting genome stability, cell division and homeostasis. We also bring to light a potential interaction between TFIIS and ΤRF1, a subunit of the shelterin complex, which protects telomeres from uncapping, suggesting that TFIIS might have a prominent role in telomere maintenance. Our data reveal the impact of TFIIS in cellular senescence, which could be potentially targeted to prolong healthy lifespan in mammals.
Language English
Subject Transcription
Transcription stress
Issue date 2022-07-29
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
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