Abstract
DNA methylation can contribute to transcriptional silencing through several transcriptionally repressive complexes, which include methyl-CpG binding domain proteins (MBDs) and histone deacetylases (HDACs). We show here that the chief enzyme that maintains mammalian DNA methylation, DNMT1, can also establish a repressive transcription complex. The non-catalytic amino terminus of DNMT1 binds to HDAC2 and a new protein, DMAP1 (for DNMT1 associated protein), and can mediate transcriptional repression. DMAP1 has intrinsic transcription repressive activity, and binds to the transcriptional co-repressor TSG101. DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase, whereas HDAC2 joins DNMT1 and DMAP1 only during late S phase, providing a platform for how histones may become deacetylated in heterochromatin following replication. Thus, DNMT1 not only maintains DNA methylation, but also may directly target, in a heritable manner, transcriptionally repressive chromatin to the genome during DNA replication.
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Acknowledgements
We thank R.-W.C. Yen, K. Wieman, E. Cameron, S. Myöhänen, R. Casero and J. Herman for technical support and advice; J. Boeke and M. Brasch for the Gene Quest yeast two-hybrid system and advice; D. Murphy and M. Delanoy for immunostaining and confocal microscopy advice; and D. Hayward and S. Zhou for the Flag-HDAC2 expression plasmid and Vero cells. This work was supported by National Institutes of Health-National Cancer Institute grants CA-43318 and CA-54396.
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Rountree, M., Bachman, K. & Baylin, S. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25, 269–277 (2000). https://doi.org/10.1038/77023
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DOI: https://doi.org/10.1038/77023
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