DNMT1 and DNMT3b cooperate to silence genes in human cancer cells

Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global m...

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Vydáno v:	Nature (London) Ročník 416; číslo 6880; s. 552 - 556
Hlavní autoři:	Rhee, Ina, Bachman, Kurtis E., Park, Ben Ho, Jair, Kam-Wing, Yen, Ray-Whay Chiu, Schuebel, Kornel E., Cui, Hengmi, Feinberg, Andrew P., Lengauer, Christoph, Kinzler, Kenneth W., Baylin, Stephen B., Vogelstein, Bert
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing 04.04.2002 Nature Publishing Group
Témata:	Amino Acid Sequence Biological and medical sciences Cancer Cellular biology Colorectal carcinoma Cyclin-Dependent Kinase Inhibitor p16 - genetics Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases - physiology DNA Methylation DNA Methyltransferase 3B DNA, Neoplasm - metabolism DNMT1 gene DNMT3a gene Gene Expression Regulation, Neoplastic Gene Silencing Gene Targeting Gene therapy General aspects Genes, Tumor Suppressor Genomics Humans Inactivation INK4a gene Insulin-Like Growth Factor II - genetics Medical sciences Molecular Sequence Data Neoplasms - enzymology Neoplasms - genetics p16 gene Promoter Regions, Genetic Tissue Inhibitor of Metalloproteinase-3 - genetics Tumor Cells, Cultured Tumors Human Enzyme Transferases Malignant tumor Inactivation Vertebrata Specificity Mammalia Enzymatic activity Methyltransferases DNA Established cell line Methylation Tumor suppressor gene
ISSN:	0028-0836, 1476-4687
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Shrnutí:	Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.
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:	10.1038/416552a