Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin

Rass, Ulrich, Ahel, Ivan and West, Stephen C (2008) Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin. The Journal of Biological Chemistry, 283 (49). pp. 33994-34001. ISSN 0021-9258

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Abstract

The human neurological disease known as ataxia with oculomotor apraxia 1 is caused by mutations in the APTX gene that encodes Aprataxin (APTX) protein. APTX is a member of the histidine triad superfamily of nucleotide hydrolases and transferases but is distinct from other family members in that it acts upon DNA. The target of APTX is 5'-adenylates at DNA nicks or breaks that result from abortive DNA ligation reactions. In this work, we show that APTX acts as a nick sensor, which provides a mechanism to assess the adenylation status of unsealed nicks. When an adenylated nick is encountered by APTX, base pairing at the 5' terminus of the nick is disrupted as the adenylate is accepted into the active site of the enzyme. Adenylate removal occurs by a two-step process that proceeds through a transient AMP-APTX covalent intermediate. These results pinpoint APTX as the first protein to adopt canonical histidine triad-type reaction chemistry for the repair of DNA.

Item Type: Article
Keywords: DNA repair, DNA single-strand break repair, abortive DNA ligation, histidine triad, AMP-DNA, DNA de-adenylation, aprataxin, neurodegenerative disease, ataxia with oculomotor apraxia 1
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > Q Science (General) > Q0179.9 Research
Q Science > Q Science (General)
Depositing User: Ulrich Rass
Date Deposited: 26 Sep 2018 09:48
Last Modified: 02 Jul 2019 14:21
URI: http://sro.sussex.ac.uk/id/eprint/79012

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