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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2009-5-25
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pubmed:abstractText |
Ataxia oculomotor apraxia-1 (AOA1) is an autosomal recessive neurodegenerative disease that results from mutations of aprataxin (APTX). APTX associates with the DNA single- and double-strand break repair machinery and is able to remove AMP from 5'-termini at DNA strand breaks in vitro. However, attempts to establish a DNA strand break repair defect in APTX-defective cells have proved conflicting and unclear. We reasoned that this may reflect that DNA strand breaks with 5'-AMP represent only a minor subset of breaks induced in cells, and/or the availability of alternative mechanisms for removing AMP from 5'-termini. Here, we have attempted to increase the dependency of chromosomal single- and double-strand break repair on aprataxin activity by slowing the rate of repair of 3'-termini in aprataxin-defective neural cells, thereby increasing the likelihood that the 5'-termini at such breaks become adenylated and/or block alternative repair mechanisms. To do this, we generated a mouse model in which APTX is deleted together with tyrosyl DNA phosphodiesterase (TDP1), an enzyme that repairs 3'-termini at a subset of single-strand breaks (SSBs), including those with 3'-topoisomerase-1 (Top1) peptide. Notably, the global rate of repair of oxidative and alkylation-induced SSBs was significantly slower in Tdp1(-/-)/Aptx(-/-) double knockout quiescent mouse astrocytes compared with Tdp1(-/-) or Aptx(-/-) single knockouts. In contrast, camptothecin-induced Top1-SSBs accumulated to similar levels in Tdp1(-/-) and Tdp1(-/-)/Aptx(-/-) double knockout astrocytes. Finally, we failed to identify a measurable defect in double-strand break repair in Tdp1(-/-), Aptx(-/-) or Tdp1(-/-)/Aptx(-/-) astrocytes. These data provide direct evidence for a requirement for aprataxin during chromosomal single-strand break repair in primary neural cells lacking Tdp1.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-10805740,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-11586299,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-11586300,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-12244316,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-15044383,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-15719174,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-15744309,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-15790557,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-15920477,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-16547001,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-16935573,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-16964241,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17224243,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17276982,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17315206,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17600775,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17889645,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17914460,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17940040,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-17948061,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-18455751,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-18467193,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-18626472,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-18836178,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-19103743,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-2320728,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-8090225,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19303373-9336444
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic,
http://linkedlifedata.com/resource/pubmed/chemical/Aptx protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Camptothecin,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Topoisomerases, Type I,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Diester Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Tdp1 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1568-7864
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
4
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pubmed:volume |
8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
760-6
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pubmed:dateRevised |
2011-8-31
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pubmed:meshHeading |
pubmed-meshheading:19303373-Animals,
pubmed-meshheading:19303373-Antineoplastic Agents, Phytogenic,
pubmed-meshheading:19303373-Astrocytes,
pubmed-meshheading:19303373-Camptothecin,
pubmed-meshheading:19303373-Cells, Cultured,
pubmed-meshheading:19303373-DNA Breaks, Single-Stranded,
pubmed-meshheading:19303373-DNA Repair,
pubmed-meshheading:19303373-DNA Topoisomerases, Type I,
pubmed-meshheading:19303373-DNA-Binding Proteins,
pubmed-meshheading:19303373-Fibroblasts,
pubmed-meshheading:19303373-Humans,
pubmed-meshheading:19303373-Mice,
pubmed-meshheading:19303373-Mice, Inbred C57BL,
pubmed-meshheading:19303373-Mice, Knockout,
pubmed-meshheading:19303373-Neurons,
pubmed-meshheading:19303373-Nuclear Proteins,
pubmed-meshheading:19303373-Phosphoric Diester Hydrolases
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pubmed:year |
2009
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pubmed:articleTitle |
Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin.
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pubmed:affiliation |
Genome Damage and Stability Centre, University of Sussex, Brighton, BN1 9RQ, UK. smfame20@sussex.ac.uk
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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