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Molecular and Cellular Biology, April 2004, p. 3387-3395, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3387-3395.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mbd1 Is Recruited to both Methylated and Nonmethylated CpGs via Distinct DNA Binding Domains

Helle F. Jørgensen,1 Ittai Ben-Porath,2,{dagger} and Adrian P. Bird1*

The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom,1 Department of Cellular Biochemistry, Hebrew University Medical School, Jerusalem, Israel2

Received 17 November 2003/ Returned for modification 15 December 2003/ Accepted 22 January 2004

MBD1 is a vertebrate methyl-CpG binding domain protein (MBD) that can bring about repression of methylated promoter DNA sequences. Like other MBD proteins, MBD1 localizes to nuclear foci that in mice are rich in methyl-CpG. In methyl-CpG-deficient mouse cells, however, Mbd1 remains localized to heterochromatic foci whereas other MBD proteins become dispersed in the nucleus. We find that Mbd1a, a major mouse isoform, contains a CXXC domain (CXXC-3) that binds specifically to nonmethylated CpG, suggesting an explanation for methylation-independent localization. Transfection studies demonstrate that the CXXC-3 domain indeed targets nonmethylated CpG sites in vivo. Repression of nonmethylated reporter genes depends on the CXXC-3 domain, whereas repression of methylated reporters requires the MBD. Our findings indicate that MBD1 can interpret the CpG dinucleotide as a repressive signal in vivo regardless of its methylation status.

* Corresponding author. Mailing address: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Mayfield Rd., Edinburgh EH9 3JR, United Kingdom. Phone: 44 131 650 8695. Fax: 44 131 650 5379. E-mail: A.Bird{at}ed.ac.uk.

{dagger} Present address: The Whitehead Institute for Biomedical Research, Cambridge, Mass.

Molecular and Cellular Biology, April 2004, p. 3387-3395, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3387-3395.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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