CpG methylation is maintained in human cancer cells lacking DNMT1

Hypermethylation is associated with the silencing of tumour susceptibility genes in several forms of cancer 1 , 2 ; however, the mechanisms responsible for this aberrant methylation are poorly understood 3 , 4 . The prototypic DNA methyltransferase, DNMT1, has been widely assumed to be responsible f...

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Vydáno v:	Nature (London) Ročník 404; číslo 6781; s. 1003 - 1007
Hlavní autoři:	Rhee, Ina, Jair, Kam-Wing, Yen, Ray-Whay Chiu, Lengauer, Christoph, Herman, James G., Kinzler, Kenneth W., Vogelstein, Bert, Baylin, Stephen B., Schuebel, Kornel E.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 27.04.2000 Nature Publishing Nature Publishing Group
Témata:	5-Methylcytosine Biological and medical sciences Blotting, Southern Cancer Colorectal carcinoma Cytosine - analogs & derivatives Cytosine - metabolism Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases - deficiency DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation DNMT1 gene Gene Silencing General aspects Genes Genes, p16 Humanities and Social Sciences Humans INK4a gene letter Medical sciences Methylation multidisciplinary Pathology Science Science (multidisciplinary) Tumor Cells, Cultured Tumors Rectal disease Carcinoma Reaction specificity CpG island Carcinogenesis Genetic determinism Gene GC rich sequence Established cell line Intestinal disease Colon Tumor cell Tumor suppressor gene Human Nucleotide sequence Enzyme Transferases Malignant tumor Colonic disease Gene silencing Methyltransferases Rectum Epigenetics Digestive diseases Hypermethylation Genome Methylation
ISSN:	0028-0836, 1476-4687
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Shrnutí:	Hypermethylation is associated with the silencing of tumour susceptibility genes in several forms of cancer 1 , 2 ; however, the mechanisms responsible for this aberrant methylation are poorly understood 3 , 4 . The prototypic DNA methyltransferase, DNMT1, has been widely assumed to be responsible for most of the methylation of the human genome, including the abnormal methylation found in cancers 5 , 6 . To test this hypothesis, we disrupted the DNMT1 gene through homologous recombination in human colorectal carcinoma cells. Here we show that cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation. Although juxtacentromeric satellites became significantly demethylated, most of the loci that we analysed, including the tumour suppressor gene p16 INK4a , remained fully methylated and silenced. These results indicate that DNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DNMT1 can maintain the methylation of most of the genome.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0028-0836 1476-4687
DOI:	10.1038/35010000