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DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci
M R Rountree1, K E Bachman, S B Baylin
1The Johns Hopkins Oncology Center, Tumor Biology Laboratory, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. rountree@jhmi.edu
Nature Genetics
|July 11, 2000
Summary
DNA methyltransferase 1 (DNMT1) not only maintains DNA methylation but also forms repressive complexes. DNMT1 targets transcriptionally repressive chromatin during DNA replication, influencing gene silencing.
Area of Science:
- Epigenetics
- Molecular Biology
- Genetics
Background:
- DNA methylation is crucial for transcriptional silencing, involving complexes like methyl-CpG binding domain proteins (MBDs) and histone deacetylases (HDACs).
- The primary enzyme for maintaining mammalian DNA methylation is DNMT1.
Purpose of the Study:
- To investigate the role of DNMT1 in establishing transcriptionally repressive complexes.
- To identify novel proteins interacting with DNMT1 in transcriptional repression.
Main Methods:
- Co-immunoprecipitation assays to identify protein interactions.
- Analysis of protein localization during the S phase of the cell cycle.
- Assays to determine the transcriptional repressive activity of identified complexes.
Main Results:
- DNMT1's non-catalytic amino terminus binds to HDAC2 and a novel protein, DMAP1 (DNMT1 associated protein).
- DMAP1 exhibits intrinsic transcription repressive activity and interacts with TSG101.
- DMAP1 localizes to replication foci with DNMT1 throughout S phase, while HDAC2 joins later in S phase.
Conclusions:
- DNMT1 actively participates in forming transcriptionally repressive complexes beyond maintaining DNA methylation.
- The DNMT1-DMAP1-HDAC2 complex provides a mechanism for targeting repressive chromatin to the genome during DNA replication.
- This suggests a heritable mechanism for epigenetic regulation following DNA replication.