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TET3 IMPACTS CARDIAC FIBROSIS PARTIALLY VIA REGULATION OF DNA DAMAGE RESPONSE

by Sandip Kumar Rath
Doctoral thesis
Date of Examination:2020-01-13
Date of issue:2020-02-12
Advisor:Prof. Dr. Elisabeth Zeisberg
Referee:Prof. Dr. Dörthe Katschinski
Referee:PD Dr. Laura C. Zelarayán
crossref-logoPersistent Address: http://dx.doi.org/10.53846/goediss-7851

 

 

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Abstract

English

Activation and proliferation of cardiac fibroblasts are the prime mediators of cardiac fibrosis. Existing studies show that ROS and inflammatory cytokines produced during fibrosis not only signal proliferative stimuli but also contribute to DNA damage. Therefore, as a prerequisite to maintain sustained proliferation in fibroblasts, activation of distinct DNA repair mechanism is essential. We have previously shown a protective epigenetic role of TET3 in organ fibrosis. Here, we demonstrate that TET3 additionally impacts DNA damage response (DDR) mechanisms via orchestrating checkpoint-assisted homologous recombination (HR)-mediated DDR, and that TGF-ß, in combination with lack of TET3 in cardiac fibrosis, leads to an increase of a checkpoint-arrest independent non-homologous end joining (NHEJ) DDR. Finally, we provide evidence that overexpression of TET3 reduces the increased proliferation rate of fibrotic fibroblasts by shifting the DDR response from NHEJ to HR.
Keywords: TET3; DNA damage; DNA repair; Cardiac fibroblasts
 

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