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Human Molecular Genetics Advance Access originally published online on March 25, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 10 1081-1093
DOI: 10.1093/hmg/ddh122
Human Molecular Genetics, Vol. 13, No. 10 © Oxford University Press 2004; all rights reserved

Aprataxin, a novel protein that protects against genotoxic stress

Nuri Gueven1,*, Olivier J. Becherel1, Amanda W. Kijas1, Philip Chen1, Orla Howe1, Jeanette H. Rudolph2, Richard Gatti3, Hidetoshi Date4, Osamu Onodera4, Gisela Taucher-Scholz2 and Martin F. Lavin1,5

1The Queensland Institute of Medical Research, Herston, Qld 4029, Australia, 2Gesellschaft für Schwerionenforschung mbH, Planckstr. 1, 64291 Darmstadt, Germany, 3UCLA School of Medicine, Department of Pathology, Los Angeles, CA 90095-1732, USA, 4Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan and 5Central Clinical School, University of Queensland, Brisbane, Qld 4006, Australia

Received February 17, 2004; Revised March 15, 2004; Accepted March 22, 2004

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.

* To whom correspondence should be addressed at: Radiation Biology and Oncology, The Queensland Institute of Medical Research, 300 Herston Rd, Herston, Qld 4029, Australia. Tel: +61 733620341; Fax: +61 733620106; Email: nurig{at}qimr.edu.au


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