The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.

Ahel, Ivan, Rass, Ulrich, El-Khamisy, Sherif F, Katyal, Sachin, Clements, Paula M, McKinnon, Peter J, Caldecott, Keith W and West, Stephen C (2006) The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature, 443. pp. 713-716. ISSN 0028-0836

Full text not available from this repository.

Abstract

Ataxia oculomotor apraxia-1 (AOA1) is a neurological disorder caused by mutations in the gene (APTX) encoding aprataxin1, 2. Aprataxin is a member of the histidine triad (HIT) family of nucleotide hydrolases and transferases3, 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, respectively4, 5, 6, 7, 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 aberrations4, 5, 8. 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.

Item Type: Article
Additional Information: My group (myself plus two post docs) contributed to both the execution and design of this work, and provided both data for specific figures and critical cell model systems for the overall project.
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Sherif El-Khamisy
Date Deposited: 06 Feb 2012 20:42
Last Modified: 02 Apr 2012 14:08
URI: http://sro.sussex.ac.uk/id/eprint/27635
📧 Request an update