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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates
Nature, Volume 443, No. 7112, Year 2006
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Description
Ataxia oculomotor apraxia-1 (AOA1) is a neurological disorder caused by mutations in the gene (APTX) encoding aprataxin. Aprataxin is a member of the histidine triad (HIT) family of nucleotide hydrolases and transferases, and inactivating mutations are largely confined to this HIT domain. Aprataxin associates with the DNA repair proteins XRCC1 and XRCC4, which are partners of DNA ligase III and ligase IV, respectively, suggestive of a role in DNA repair. Consistent with this, APTX-defective cell lines are sensitive to agents that cause single-strand breaks and exhibit an increased incidence of induced chromosomal aberrations. It is not, however, known whether aprataxin has a direct or indirect role in DNA repair, or what the physiological substrate of aprataxin might be. Here we show, using purified aprataxin protein and extracts derived from either APTX-defective chicken DT40 cells or Aptx-/- mouse primary neural cells, that aprataxin resolves abortive DNA ligation intermediates. Specifically, aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5′-phosphate termini at single-strand nicks and gaps, resulting in the production of 5′-phosphate termini that can be efficiently rejoined. These data indicate that neurological disorders associated with APTX mutations may be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events. © 2006 Nature Publishing Group.
Authors & Co-Authors
Ahel, Ivan
United Kingdom, London
Cancer Research uk
Rass, Ulrich
United Kingdom, London
Cancer Research uk
El-Khamisy, Sherif F.
United Kingdom, Brighton
Genome Damage and Stability Centre
Egypt, Cairo
Faculty of Pharmacy - Ain Shams University
Katyal, Sachin
United States, Memphis
St. Jude Children's Research Hospital
Clements, Paula M.
United Kingdom, Brighton
Genome Damage and Stability Centre
McKinnon, Peter J.
United States, Memphis
St. Jude Children's Research Hospital
Caldecott, Keith W.
United Kingdom, Brighton
Genome Damage and Stability Centre
West, Stephen C.
United Kingdom, London
Cancer Research uk
Statistics
Citations: 373
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1038/nature05164
ISSN:
00280836
e-ISSN:
14764687
Research Areas
Cancer
Genetics And Genomics
Study Design
Cohort Study