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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2004-7-2
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pubmed:abstractText |
Timing of DNA replication initiation is dependent on S-phase-promoting kinase (SPK) activity at discrete origins and the simultaneous function of many replicons. DNA damage prevents origin firing through the ATM- and ATR-dependent inhibition of Cdk2 and Cdc7 SPKs. Here, we establish that modulation of ATM- and ATR-signalling pathways controls origin firing in the absence of DNA damage. Inhibition of ATM and ATR with caffeine or specific neutralizing antibodies, or upregulation of Cdk2 or Cdc7, promoted rapid and synchronous origin firing; conversely, inhibition of Cdc25A slowed DNA replication. Cdk2 was in equilibrium between active and inactive states, and the concentration of replication protein A (RPA)-bound single-stranded DNA (ssDNA) correlated with Chk1 activation and inhibition of origin firing. Furthermore, ATM was transiently activated during ongoing replication. We propose that ATR and ATM regulate SPK activity through a feedback mechanism originating at active replicons. Our observations establish that ATM- and ATR-signalling pathways operate during an unperturbed cell cycle to regulate initiation and progression of DNA synthesis, and are therefore poised to halt replication in the presence of DNA damage.
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pubmed:grant |
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pubmed:commentsCorrections |
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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/ATR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies,
http://linkedlifedata.com/resource/pubmed/chemical/Atr protein, Xenopus,
http://linkedlifedata.com/resource/pubmed/chemical/CDC2-CDC28 Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/CDC25A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CDC7 protein, Xenopus,
http://linkedlifedata.com/resource/pubmed/chemical/CDC7 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CDK2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Caffeine,
http://linkedlifedata.com/resource/pubmed/chemical/Cdk2 protein, Xenopus,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Extracts,
http://linkedlifedata.com/resource/pubmed/chemical/Checkpoint kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Single-Stranded,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RPA1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Replication Protein A,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Xenopus Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/ataxia telangiectasia mutated...,
http://linkedlifedata.com/resource/pubmed/chemical/cdc25 Phosphatases
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1465-7392
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
6
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
648-55
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:15220931-Animals,
pubmed-meshheading:15220931-Antibodies,
pubmed-meshheading:15220931-CDC2-CDC28 Kinases,
pubmed-meshheading:15220931-Caffeine,
pubmed-meshheading:15220931-Cell Cycle Proteins,
pubmed-meshheading:15220931-Cell Extracts,
pubmed-meshheading:15220931-Cell-Free System,
pubmed-meshheading:15220931-Cyclin-Dependent Kinase 2,
pubmed-meshheading:15220931-DNA, Single-Stranded,
pubmed-meshheading:15220931-DNA Damage,
pubmed-meshheading:15220931-DNA Replication Timing,
pubmed-meshheading:15220931-DNA-Binding Proteins,
pubmed-meshheading:15220931-Feedback, Physiological,
pubmed-meshheading:15220931-Female,
pubmed-meshheading:15220931-Humans,
pubmed-meshheading:15220931-Oocytes,
pubmed-meshheading:15220931-Protein Kinases,
pubmed-meshheading:15220931-Protein-Serine-Threonine Kinases,
pubmed-meshheading:15220931-Replication Protein A,
pubmed-meshheading:15220931-Signal Transduction,
pubmed-meshheading:15220931-Tumor Suppressor Proteins,
pubmed-meshheading:15220931-Xenopus Proteins,
pubmed-meshheading:15220931-Xenopus laevis,
pubmed-meshheading:15220931-cdc25 Phosphatases
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pubmed:year |
2004
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pubmed:articleTitle |
ATR and ATM regulate the timing of DNA replication origin firing.
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pubmed:affiliation |
Integrated Program in Cellular, Molecular, and Biophysical Studies, and Department of Genetics and Development, Hammer Health Sciences Center, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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