title: A novel form of ataxia oculomotor apraxia characterized by oxidative stress and apoptosis resistance.
abstract: 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 patient cells. There was also evidence for oxidative damage to proteins and lipids. Although these cells were hypersensitive to DNA damaging agents, the mode of death was not by apoptosis. These cells were also resistant to TRAIL-induced death. Consistent with these observations, failure to observe a decrease in mitochondrial membrane potential, reduced cytochrome c release and defective apoptosis-inducing factor translocation to the nucleus was observed. Apoptosis resistance and PARP-1 hyperactivation were overcome by incubating the patient's cells with antioxidants. These results provide evidence for a novel form of AOA characterized by sensitivity to DNA damaging agents, oxidative stress, PARP-1 hyperactivation but resistance to apoptosis.
authors.affiliation: Department of Cancer and Cell Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Gueven
authors.forename: O J
authors.initials: OJ
authors.lastname: Becherel
authors.forename: O
authors.initials: O
authors.lastname: Howe
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: J-F
authors.initials: JF
authors.lastname: Haince
authors.forename: M-E
authors.initials: ME
authors.lastname: Ouellet
authors.forename: G G
authors.initials: GG
authors.lastname: Poirier
authors.forename: N
authors.initials: N
authors.lastname: Waterhouse
authors.forename: M
authors.initials: M
authors.lastname: Fusser
authors.forename: B
authors.initials: B
authors.lastname: Epe
authors.forename: J M
authors.initials: JM
authors.lastname: de Murcia
authors.forename: G
authors.initials: G
authors.lastname: de Murcia
authors.forename: C H
authors.initials: CH
authors.lastname: McGowan
authors.forename: R
authors.initials: R
authors.lastname: Parton
authors.forename: C
authors.initials: C
authors.lastname: Mothersill
authors.forename: P
authors.initials: P
authors.lastname: Grattan-Smith
authors.forename: M F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D001072:Apraxias / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001259:Ataxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D002478:Cells, Cultured; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011839:Radiation, Ionizing; D026361:Reactive Nitrogen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D026361:Reactive Nitrogen Species; D008769:Methylnitronitrosoguanidine; D016685:Mitomycin; D005047:Etoposide; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002166:Camptothecin