Rountree et al. (2000) identified the DMAP1 protein in a yeast 2-hybrid screen of mouse brain and embryonic cDNA libraries using the first 1,125 amino acids of DNMT1 (126375) as bait. They cloned the DMAP1 cDNA from a human adult brain cDNA library. The 467-amino acid DMAP1 protein shares approximately 98% amino acid conservation with the homologous mouse protein and contains a putative nuclear localization signal and a predicted coiled-coil domain.

The eukaryotic cell faces a major mechanistic challenge during replication of its genome in that newly synthesized DNA must be rapidly assembled into the proper chromatin configuration to foster or inhibit transcription. The eukaryotic genome consists of transcriptionally active and inactive domains, which are generally characterized by regions of euchromatin and heterochromatin, respectively. Euchromatic regions tend to replicate early in S phase and are generally characterized by the presence of actively transcribing, or transcription-ready, genes, a paucity of DNA methylation, and an open chromatin configuration containing hyperacetylated histones. Alternatively, the heterochromatic regions (including pericentromeric and telomeric repeats), the inactive X chromosome, and transcriptionally silent alleles of selected imprinted genes are associated with a lack of transcriptional activity, heavy CpG methylation, and compact chromatin with hypoacetylated histones, and tend to replicate in later stages of S phase. In these chromatin configurations, the inheritance of the epigenetic 'mark' of methylation appears to be an important component of transcriptional silencing. DNA methylation can contribute to transcriptional silencing through several transcriptionally repressive complexes, which include methyl-CpG-binding domain proteins (e.g., MBD1; 156535) and histone deacetylases (e.g., HDAC1; 601241). Rountree et al. (2000) showed that the chief enzyme that maintains mammalian DNA methylation, DNMT1 (126375), can also establish a repressive transcription complex consisting of DNMT1, HDAC2 (605164), and DMAP1. DMAP1 interacts directly with the first 120 amino acids of DNMT1. Rountree et al. (2000) demonstrated that DMAP1 can repress transcription independently of histone deacetylase activity. DNMT1, HDAC2, and DMAP1 form a complex in vivo, and DMAP1 can interact directly with the transcriptional corepressor TSG101 (601387). 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.

In order to clarify the role of DAXX (603186) in IFNA (147660)/IFNB (147640)-mediated suppression of B-cell development and apoptosis, Muromoto et al. (2004) used a yeast 2-hybrid screen and identified DMAP1 as a DAXX-interacting protein. Immunoprecipitation and Western blot analysis with DAXX mutants showed that the N terminus of DAXX interacts with the C terminus of DMAP. Immunoblot analysis and confocal microscopy demonstrated that the DAXX-DMAP complex interacts with DNMT1 in the nucleus. Transient expression of DAXX or DMAP1 caused repression of glucocorticoid receptor (GCCR; 138040)-mediated transcription. Muromoto et al. (2004) concluded that the linkage between DAXX and DNMT1 forms an efficient transcription repression complex in the nucleus.

The NuA4 histone acetyltransferase (HAT) complex is responsible for acetylation of the N-terminal tails of histone H4 (see 602822) and H2A (see 613499) in yeast. Its catalytic subunit, Esa1, is homologous to human TIP60 (HTATIP; 601409). Using affinity purification, Western blot analysis, cell fractionation, immunoprecipitation, and mass spectrometry, Doyon et al. (2004) found that TIP60 and its splice variant, TIP60B/PLIP, were part of a multisubunit NuA4 complex with HAT activity in several human cell lines. They identified human homologs for 11 of the 12 yeast NuA4 subunits, including DMAP1. DMAP1 was also present in a distinct complex harboring SWI2 (SMARCA2; 600014)-related ATPase activity.

Using RNA interference in mouse embryonic stem (ES) cells, Fazzio et al. (2008) found that depletion of any of 7 components of the Tip60-p400 (EP400; 606265) HAT and nucleosome remodeling complex, including Dmap1, caused the same phenotype. Unlike normal ES cells, which grow in spherical 3-dimensional colonies, ES cells depleted of any the 7 Tip60-p400 HAT components showed a flattened and elongated morphology, with monolayer growth and reduced cell-cell contacts. These knockdown cells continued to cycle, with reduced cells in S phase and increased cells in G2 phase. The effect of Tip60-p400 HAT component knockdown was unique to ES cells, as negligible changes were observed following knockdown in mouse embryonic fibroblasts.