The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

Abstract

DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

“…30 This observation has, however, been refuted by the analysis of large FRDA patient cohort data and by revisiting the liver tumor pathology in the conditional knockout frataxin mouse model. 31 Frataxin has been proposed to be a tumor suppressor gene by Guccini et al , 32 who showed that frataxin modulates P53 expression in tumors in response to hypoxia.…”

Iron and cancer: more ore to be mined

“…As overexpression of frataxin also increased oxidative metabolism (as measured by increased mitochondrial membrane potential, cell respiration and ATP content), it was speculated that frataxin may inhibit tumour formation by reversing the metabolic switch to aerobic glycolysis (the Warburg effect), which occurs in many cancer cells 95 . Whether frataxin indeed exerts its effects by modifying metabolism and/or by other mechanisms, including the prevention of oxidative DNA damage and fostering DNA repair 96 , has not yet been definitively addressed.…”

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

“…2 and 4). It has been noted for both yeast and human cells that frataxin-deficient cells show increased sensitivity to nuclear DNA damage (Karthikeyan et al 2002;Thierbach et al 2010). This effect has now been explained as a general consequence of ISC (and CIA) protein defects, which hamper the assembly of critical Fe/S components of DNA metabolism such as replicative DNA polymerases and numerous DNA helicases involved in DNA repair (Gari et al 2012;Stehling et al 2012).…”