Human Molecular Genetics Advance Access published online on March 25, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh122
© 2004 by Oxford University Press
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1 Radiation Biology and Oncology, The Queensland Institute of Medical Research, 300 Herston Rd, Herston Qld 4029, Australia
* To whom correspondence should be addressed. E-mail: nurig{at}qimr.edu.au.
Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia (A-T), 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 nucleolus. Mutations in the APTX gene destabilize the Aprataxin protein and EGFP-Aprataxin fusion constructs, 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 H2O2 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 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.
Article
Aprataxin, a novel protein that protects against genotoxic stress
2 The Queensland Institute of Medical Research, Herston Qld 4029, Australia
3 Gesellschaft für Schwerionenforschung mbH, Planckstr. 1, 64291 Darmstadt, Germany
4 UCLA School of Medicine, Department of Pathology, Los Angeles, Ca 90095-1732, USA
5 Department of Neurology, Brain research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan
6 The Queensland Institute of Medical Research, Herston Qld 4029, Australia; Central Clinical School, University of Queensland, Brisbane Qld 4006, Australia
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