title: Aprataxin, a novel protein that protects against genotoxic stress.
abstract: Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia, a syndrome characterized by abnormal responses to double-strand DNA breaks and genome instability. The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair. We demonstrate that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilize the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generate highly unstable products. Cells from AOA1 patients are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA but there is no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA. We also demonstrate that aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and that it co-localizes with XRCC1 along charged particle tracks on chromatin. These results demonstrate that aprataxin influences the cellular response to genotoxic stress very likely by its capacity to interact with a number of proteins involved in DNA repair.
authors.affiliation: Radiation Biology and Oncology, The Queensland Institute of Medical Research, Herston, Australia. nurig@qimr.edu.au
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Kijas
authors.forename: Philip
authors.initials: P
authors.lastname: Chen
authors.forename: Orla
authors.initials: O
authors.lastname: Howe
authors.forename: Jeanette H
authors.initials: JH
authors.lastname: Rudolph
authors.forename: Richard
authors.initials: R
authors.lastname: Gatti
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Gisela
authors.initials: G
authors.lastname: Taucher-Scholz
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D001072:Apraxias / Q000235:genetics*; D001259:Ataxia / Q000235:genetics*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000648:ultrastructure; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D020125:Mutation, Missense; D019913:Nuclear Localization Signals / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011839:Radiation, Ionizing; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C438188:APTX protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D008698:Mesylates; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C045880:methanesulfonic acid; D016685:Mitomycin; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases