CpG methylation is maintained in human cancer cells lacking DNMT1

Ina Rhee, Kam-Wing Jair, Ray-Whay Chiu Yen, Christoph Lengauer, James G. Herman, Kenneth W. Kinzler, Bert Vogelstein, Stephen B. Baylin and Kornel E. Schuebel ()
Additional contact information
Ina Rhee: The Howard Hughes Medical Institute,
Kam-Wing Jair: The Johns Hopkins Oncology Center
Ray-Whay Chiu Yen: The Johns Hopkins Oncology Center
Christoph Lengauer: The Johns Hopkins Oncology Center
James G. Herman: The Johns Hopkins Oncology Center
Kenneth W. Kinzler: The Johns Hopkins Oncology Center
Bert Vogelstein: The Howard Hughes Medical Institute,
Stephen B. Baylin: The Johns Hopkins Oncology Center
Kornel E. Schuebel: The Johns Hopkins Oncology Center

Nature, 2000, vol. 404, issue 6781, 1003-1007

Abstract: Abstract Hypermethylation is associated with the silencing of tumour susceptibility genes in several forms of cancer1,2; however, the mechanisms responsible for this aberrant methylation are poorly understood3,4. 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 cancers5,6. 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 p16INK4a, 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.

Date: 2000
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DOI: 10.1038/35010000

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