DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.
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.
Rountree
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MR
The Johns Hopkins Oncology Center, Tumor Biology Laboratory, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. rountree@jhmi.edu
Bachman
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KE
Baylin
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SB
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014709:Vero Cells; D000099177:Tsg101 Protein
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D006836:Hydro-Lyases; D012097:Repressor Proteins; D014157:Transcription Factors; D000099177:Tsg101 Protein; C411744:DMAP1 protein, human; C485852:Dmap1 protein, mouse; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C533424:Hdac2 protein, mouse; C021434:imidazoleglycerolphosphate dehydratase