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J. Biol. Chem., Vol. 280, Issue 18, 17986-17991, May 6, 2005

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Inactivation of Dnmt3b in Mouse Embryonic Fibroblasts Results in DNA Hypomethylation, Chromosomal Instability, and Spontaneous Immortalization^*

Jonathan E. Dodge, Masaki Okano¶, Fred Dick||**, Naomi Tsujimoto, Taiping Chen, Shumei Wang, Yoshihide Ueda, Nick Dyson||, and En Li¶¶

From the Cardiovascular Research Center and ^||Cancer Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and ^¶RIKEN Center for Developmental Biology, 650-0047 Kobe, Japan

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 primary and spontaneously immortalized Dnmt3b-deficient MEFs because the p53 protein was inducible by DNA damage. Interestingly, protein levels of the cyclindependent 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.

Received for publication, November 23, 2004 , and in revised form, February 23, 2005.

^* This work was supported in part by National Institutes of Health Grants CA82389 and GM52106 (to E. L). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an institutional National Research Service Award postdoctoral fellowship awarded to the Cardiovascular Research Center at Massachusetts General Hospital.

^** Supported by fellowships from the Leukemia and Lymphoma Society and the Medical Foundation (Charles A. King Trust).

Present address: Dept. of Biochemistry, University of Western Ontario, 790 Commissioners Rd. East, London, Ontario N6A 4L6, Canada.

Present address: Novartis Institutes for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139.

^¶¶ To whom correspondence should be addressed. Tel.: 617-871-7072; Fax: 617-871-7263; E-mail: en.li{at}pharma.novartis.com.

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