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Molecular and Cellular Biology, October 2004, p. 9048-9058, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9048-9058.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

Taiping Chen,1,2 Naomi Tsujimoto,1,2 and En Li1,2*

Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown,1 Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts2

Received 5 May 2004/ Returned for modification 8 June 2004/ Accepted 29 June 2004

Dnmt3a and Dnmt3b are responsible for the establishment of DNA methylation patterns during development. These proteins contain, in addition to a C-terminal catalytic domain, a unique N-terminal regulatory region that harbors conserved domains, including a PWWP domain. The PWWP domain, characterized by the presence of a highly conserved proline-tryptophan-tryptophan-proline motif, is a module of 100 to 150 amino acids found in many chromatin-associated proteins. However, the function of the PWWP domain remains largely unknown. In this study, we provide evidence that the PWWP domains of Dnmt3a and Dnmt3b are involved in functional specialization of these enzymes. We show that both endogenous and green fluorescent protein-tagged Dnmt3a and Dnmt3b are particularly concentrated in pericentric heterochromatin. Mutagenesis analysis indicates that their PWWP domains are required for their association with pericentric heterochromatin. Disruption of the PWWP domain abolishes the ability of Dnmt3a and Dnmt3b to methylate the major satellite repeats at pericentric heterochromatin. Furthermore, we demonstrate that the Dnmt3a PWWP domain has little DNA-binding ability, in contrast to the Dnmt3b PWWP domain, which binds DNA nonspecifically. Collectively, our results suggest that the PWWP domains of Dnmt3a and Dnmt3b are essential for targeting these enzymes to pericentric heterochromatin, probably via a mechanism other than protein-DNA interactions.

* Corresponding author. Mailing address: Novartis Institutes for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139. Phone: (617) 871-7072. Fax: (617) 871-7263. E-mail: en.li{at}pharma.novartis.com.

Molecular and Cellular Biology, October 2004, p. 9048-9058, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.9048-9058.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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