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The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates (CROSBI ID 124828)

Prilog u časopisu | Pismo (znanstveno) | međunarodna recenzija

Ahel, Ivan ; Rass, Ulrich ; El-Khamisy, Sherif F. ; Katyal, Sachin ; Clements, Paula M. ; McKinnon, Peter J. ; Caldecott, Keith W. ; West, Stephen C The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates // Nature, 443 (2006), 713-716. doi: 10.1038/nature05164

Podaci o odgovornosti

Ahel, Ivan ; Rass, Ulrich ; El-Khamisy, Sherif F. ; Katyal, Sachin ; Clements, Paula M. ; McKinnon, Peter J. ; Caldecott, Keith W. ; West, Stephen C

engleski

The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates

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.

Ataxia oculomotor apraxia-1 (AOA1) ; unrepaired DNA strand breaks

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Podaci o izdanju

443

2006.

713-716

objavljeno

0028-0836

1476-4687

10.1038/nature05164

Povezanost rada

Biologija

Poveznice