Nucleic Acids Research Advance Access originally published online on May 22, 2007
Nucleic Acids Research 2007 35(11):3797-3809; doi:10.1093/nar/gkm158
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Nucleic Acids Research, 2007, Vol. 35, No. 11 3797-3809
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends
1Department of Neurology, Clinical Neuroscience Branch, 2Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Center for Bioresource-Based Research, Brain Research Institute, 3Department of Structural Pathology Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Niigata 951-8122, Japan and 4Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo113-8655, Japan
*To whom correspondence should be addressed. Tel: 81 25 227 0665; Fax: 81 25 223 6646; Email: onodera{at}bri.niigata-u.ac.jp
Received December 14, 2006. Revised March 1, 2007. Accepted March 1, 2007.
Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-
, ß-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-, ß-unsaturated aldehyde ends, and can act with DNA polymerase ß and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.
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