Linking DNA replication, DNA Damage Response, and oxidative stress to GAA-repeat instability in Friedreich’s Ataxia disease

Cibio Seminar

12 November 2019
Versione stampabile

Date&Time: 12th November 2019 - h. 2:30 pm
Location: Polo Ferrari 2, Via Sommarive 9 (Povo) - Room B103

Antonella Russo
Department of Molecular Medicine, University of Padova


Friedreich's Ataxia (FRDA) is an autosomal recessive disease, caused by transcriptional inhibition of the Frataxin (FXN) gene, after expansion of an intronic GAA-repeat. Depletion of Frataxin, a mitochondrial protein, leads to a constitutive unbalanced production of reactive oxygen species (ROS), a condition that could affect the DNA damage response (DDR) and contribute to somatic GAA-repeat instability. Using different in vitro assays, we explored the response of FRDA cells to the induction of oxidative stress. Unexpectedly, we observed that FRDA cells are less responsive than normal ones to exogenous sources of oxidative stress. Recently, we demonstrated that the expanded GAA-repeat is cause of replication stress (Stevanoni, Palumbo, and Russo, 2016, PLOS Genet. 12, e1006201). With the goal to clarify the relevance of replication/transcription conflicts for FRDA mutation, we are currently investigating whether FXN transcription is modulated along the cell cycle, using RNA-FISH for monitoring the elongation of FXN pre-mRNA.
The above tightly related issues contribute to unravel the potential involvement of cellular events, normally associated with gene expression and genome integrity, in the dynamic changes of the GAA-repeat.