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Human Molecular Genetics Advance Access originally published online on July 30, 2009
Human Molecular Genetics 2009 18(21):4102-4117; doi:10.1093/hmg/ddp359
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage

Janelle L. Harris1,2, Burkhard Jakob3, Gisela Taucher-Scholz3, Grigory L. Dianov4, Olivier J. Becherel1 and Martin F. Lavin1,5,*

1 Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, Queensland 4029, Australia 2 Queensland University of Technology, School of Life Sciences, Brisbane, Queensland 4000, Australia 3 GSI Helmholtzzentrum für Schwerionenforschung GmBH, Planckstr. 1, 64291 Darmstadt, Germany 4 Medical Research Council Radiation Oncology and Biology Unit, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK 5 University of Queensland Centre for Clinical Research, Brisbane, Australia

* To whom correspondence should be addressed at: Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. Tel: +61 733620341; Fax: +61 733620106; Email: martin.lavin{at}qimr.edu.au

Received February 24, 2009; Accepted July 28, 2009

Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1 (AOA1), is a DNA repair protein that processes the product of abortive ligations, 5' adenylated DNA. In addition to its interaction with the single-strand break repair protein XRCC1, aprataxin also interacts with poly-ADP ribose polymerase 1 (PARP-1), a key player in the detection of DNA single-strand breaks. Here, we reveal reduced expression of PARP-1, apurinic endonuclease 1 (APE1) and OGG1 in AOA1 cells and demonstrate a requirement for PARP-1 in the recruitment of aprataxin to sites of DNA breaks. While inhibition of PARP activity did not affect aprataxin activity in vitro, it retarded its recruitment to sites of DNA damage in vivo. We also demonstrate the presence of elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP-1, APE-1 and OGG1 in the DNA damage response. These data support both direct and indirect modulating functions for aprataxin on base excision repair.


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