0000000000619892
AUTHOR
Markus Fusser
A novel form of ataxia oculomotor apraxia characterized by oxidative stress and apoptosis resistance
Several different autosomal recessive genetic disorders characterized by ataxia with oculomotor apraxia (AOA) have been identified with the unifying feature of defective DNA damage recognition and/or repair. We describe here the characterization of a novel form of AOA showing increased sensitivity to agents that cause single-strand breaks (SSBs) in DNA but having no gross defect in the repair of these breaks. Evidence for the presence of residual SSBs in DNA was provided by dramatically increased levels of poly (ADP-ribose)polymerase (PARP-1) auto-poly (ADP-ribosyl)ation, the detection of increased levels of reactive oxygen/nitrogen species (ROS/RNS) and oxidative damage to DNA in the patie…
The Friedreich's Ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals
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 frata…
Spontaneous mutagenesis in Csb(m/m)Ogg1⁻(/)⁻ mice is attenuated by dietary resveratrol.
Oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are generated endogenously in apparently all living cells. The defect of the repair of 8-oxoG in Csb m/m Ogg1 ―/― mice results in elevated basal levels of these lesions and increased frequencies of spontaneous mutations, which initiate tumorigenesis in the liver if cell proliferation is stimulated. Here, we describe that the phytoalexin resveratrol, applied either for 7 days per gavage (100 mg/kg body wt) or for 3―9 months in the diet (0.04% ad libitum), reduces the endogenous oxidative DNA base damage in the livers of the Csb m/m Ogg1 ―/― mice by 20―30% (P < 0.01). A small but consistent effect is also observed in the wi…