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Papers In Press, published online ahead of print March 8, 2005
Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, MA 02139
Corresponding Author: en.li{at}pharma.novartis.com
DNA hypomethylation is a hallmark of many types of solid tumors. However, it remains elusive how DNA hypomethylation may contribute to tumorigenesis. In this study, we have investigated how targeted disruption of the DNA methyltransferases Dnmt3a and Dnmt3b affects the growth of mouse embryonic fibroblasts (MEFs). Our studies led to the following observations. (1) Constitutive or conditional deletion of Dnmt3b, but not Dnmt3a, resulted in partial loss of DNA methylation throughout the genome, suggesting that Dnmt3b, in addition to the major maintenance methyltransferase Dnmt1, is required for maintaining DNA methylation in MEF cells. (2) Dnmt3b-deficient MEF cells showed aneuploidy and polyploidy, chromosomal breaks and fusions. (3) Inactivation of Dnmt3b resulted in either premature senescence or spontaneous immortalization of MEF cells. (4) The G1 to S-phase checkpoint was intact in early-passage and spontaneously immortalized Dnmt3b-deficient MEFs, as the p53 protein was inducible by DNA damage. Interestingly, protein levels of the cyclin-dependent kinase inhibitor p21 were increased in immortalized Dnmt3b-deficient MEFs even in the absence of p53 induction. These results suggest that DNA hypomethylation may induce genomic instability which in turn leads to spontaneous immortalization or premature senescence of Dnmt3b-deficient MEFs via a p53-independent mechanism.
J. Biol. Chem, 10.1074/jbc.M413246200
Submitted on November 23, 2004
Revised on February 23, 2005
Accepted on March 1, 2005
Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization
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