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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2010-7-27
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pubmed:abstractText |
5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal degradation of free (non-chromatin bound) DNMT1 through a mechanism which is dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues by DNMT1 itself. Thus, 5-aza-dC induces Dnmt1 degradation in wild-type mouse ES cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express Dnmt1 but lack DNA methylation (<0.7% of CpG methylated) and contain few hemi-methylated CpG sites, these being the preferred substrates for Dnmt1. We suggest that adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3 ligase activity which preferentially targets free DNMT1 molecules for degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1 degradation and reduces hypomethylation induced by 5-aza-dC.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-10555141,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-11290321,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-12397175,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-1340468,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-15215866,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-15456861,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-15899874,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-16179921,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-16963560,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-1706062,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-17322882,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-17991895,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-19129216,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-19417133,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-19502488,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-3558369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-5696931,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-6156004,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-6187927,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-8898232,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20348135-9302295
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1362-4962
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
38
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4313-24
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pubmed:dateRevised |
2010-9-30
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pubmed:meshHeading |
pubmed-meshheading:20348135-Animals,
pubmed-meshheading:20348135-Aphidicolin,
pubmed-meshheading:20348135-Azacitidine,
pubmed-meshheading:20348135-Cell Line,
pubmed-meshheading:20348135-Chromatin,
pubmed-meshheading:20348135-DNA,
pubmed-meshheading:20348135-DNA (Cytosine-5-)-Methyltransferase,
pubmed-meshheading:20348135-DNA Methylation,
pubmed-meshheading:20348135-Enzyme Inhibitors,
pubmed-meshheading:20348135-Mice,
pubmed-meshheading:20348135-Proteasome Endopeptidase Complex
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pubmed:year |
2010
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pubmed:articleTitle |
Targeting of 5-aza-2'-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme.
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pubmed:affiliation |
Breakthrough Research Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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