Aprataxin, a novel protein that protects against genotoxic stress

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 aprataxi...

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Bibliographic Details
Published in:	Human molecular genetics Vol. 13; no. 10; pp. 1081 - 1093
Main Authors:	Gueven, Nuri, Becherel, Olivier J., Kijas, Amanda W., Chen, Philip, Howe, Orla, Rudolph, Jeanette H., Gatti, Richard, Date, Hidetoshi, Onodera, Osamu, Taucher-Scholz, Gisela, Lavin, Martin F.
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 15-05-2004 Oxford Publishing Limited (England)
Subjects:	Apraxias - genetics Ataxia - genetics Ataxia Telangiectasia - genetics Ataxia Telangiectasia - metabolism Biological and medical sciences Cell Culture Techniques Chromatin - metabolism Classical genetics, quantitative genetics, hybrids DNA Damage DNA Repair DNA-Binding Proteins - analysis DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism DNA-Binding Proteins - physiology Fibroblasts - ultrastructure Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Human Humans Hydrogen Peroxide - pharmacology Mesylates - pharmacology Mitomycin - pharmacology Molecular and cellular biology Mutation, Missense Nuclear Localization Signals - genetics Nuclear Proteins - analysis Nuclear Proteins - genetics Nuclear Proteins - physiology Poly(ADP-ribose) Polymerases - metabolism Protein Binding Protein Interaction Mapping Radiation, Ionizing Syndrome Tumor Suppressor Protein p53 - metabolism X-ray Repair Cross Complementing Protein 1 Genetics Protein Stress
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Summary:	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.
Bibliography:	ark:/67375/HXZ-KRKDQLP2-9 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@qimr.edu.au istex:C483CF030ECEF96503BE97CAFE73DDA28B73B7AD local:ddh122 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0964-6906 1460-2083 1460-2083
DOI:	10.1093/hmg/ddh122