J. Biol. Chem.-2008-Rass-33994-4001.pdf (908.96 kB)
Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin
journal contribution
posted on 2023-06-09, 15:13 authored by Ulrich RassUlrich Rass, Ivan Ahel, Stephen C WestThe 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.
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- Published
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- Published version
Journal
The Journal of Biological ChemistryISSN
0021-9258Publisher
American Society for Biochemistry and Molecular BiologyExternal DOI
Issue
49Volume
283Page range
33994-34001Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
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- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-09-26First Open Access (FOA) Date
2018-09-26First Compliant Deposit (FCD) Date
2018-09-25Usage metrics
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