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Published online
doi:10.1083/jcb.200701042
The Journal of Cell Biology, Vol. 177, No. 6, 969-979
The Rockefeller University Press, 0021-9525 $30.00
© Suraweera et al.
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Article

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage



Amila Suraweera1,2, Olivier J. Becherel1, Philip Chen1, Natalie Rundle1, Rick Woods1, Jun Nakamura3, Magtouf Gatei1, Chiara Criscuolo4, Alessandro Filla4, Luciana Chessa5, Markus Fußer6, Bernd Epe6, Nuri Gueven1, and Martin F. Lavin1,2

1 Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia
2 Central Clinical Division, University of Queensland, Brisbane, QLD 4029, Australia
3 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
4 Department of Neurobiology, University of Naples, Naples, 80131, Italy
5 Department of Experimental Medicine and Pathology, University "La Sapienza," Roma, 324-00161, Italy
6 Institute of Pharmacy, University of Mainz, Mainz, 55099, Germany

Correspondence to Martin F. Lavin: martin.lavin{at}qimr.edu.au

Adefective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome.

A. Suraweera and O.J. Becherel contributed equally to this paper.

Abbreviations used in this paper: AOA, ataxia oculomotor apraxia; A-T; ataxia-telangiectasia; A-TLD, A-T–like disorder; ATM, A-T mutated; CPT, camptothecin; DSB, double-strand break; IR, ionizing radiation; MMC, mitomycin C; NFF, normal foreskin fibroblast; SSB, single-strand break.


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