DNA methyltransferase that methylates CpG residues (PubMed:17200670, PubMed:18754681, PubMed:21745816, PubMed:26070743). Preferentially methylates hemimethylated DNA (PubMed:21745816, PubMed:26070743). Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance (PubMed:17200670, PubMed:21745816).

Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication (PubMed:21745816). It is responsible for maintaining methylation patterns established in development (PubMed:21745816). DNA methylation is coordinated with methylation of histones (PubMed:16357870).

Mediates transcriptional repression by direct binding to HDAC2 (PubMed:10888872). In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9 (PubMed:18413740). Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306).

Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306)

Homodimer (PubMed:19173286). Forms a stable complex with E2F1, BB1 and HDAC1 (PubMed:10888886). Forms a complex with DMAP1 and HDAC2, with direct interaction (PubMed:10888872).

Interacts with the PRC2/EED-EZH2 complex (PubMed:16357870). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with UHRF1; promoting its recruitment to hemimethylated DNA (PubMed:21745816).

Interacts with USP7, promoting its deubiquitination (PubMed:21745816). Interacts with PCNA (PubMed:9302295). Interacts with MBD2 and MBD3 (PubMed:10947852).

Interacts with DNMT3A and DNMT3B (PubMed:12145218). Interacts with UBC9 (PubMed:19450230). Interacts with CSNK1D (By similarity).

Interacts with HDAC1 (By similarity). Interacts with BAZ2A/TIP5 (By similarity). Interacts with SIRT7 (By similarity).

Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with L3MBTL3 and DCAF5; the interaction requires DNMT1 methylation at Lys-142 and is necessary to target DNMT1 for ubiquitination by the CRL4-DCAF5 E3 ubiquitin ligase complex and proteasomal degradation (PubMed:29691401). Interacts with PHF20L1; the interaction requires DNMT1 methylation at Lys-142 and protects DNMT1 from ubiquitination and proteasomal degradation (PubMed:24492612)

Ubiquitous; highly expressed in fetal tissues, heart, kidney, placenta, peripheral blood mononuclear cells, and expressed at lower levels in spleen, lung, brain, small intestine, colon, liver, and skeletal muscle. Isoform 2 is less expressed than isoform 1

The RFTS domain specifically recognizes and binds histone H3 monoubiquitinated at two sites, either at 'Lys-14', 'Lys-18' and/or 'Lys-23' (H3K14ub, H3K18ub and H3K23ub, respectively) (PubMed:29053958). These histone marks are present at hemimethylated DNA sites at replication forks and act as docking site for DNMT1 (PubMed:29053958). In absence of H3K14ub, H3K18ub and H3K23ub chromatin marks, the RFTS domain inhibits the DNA methyltransferase activity by forming hydrogen bonds with the catalytic center (PubMed:29053958).

Binding to ubiquitinated histones relieves inhibition (PubMed:29053958)

The CXXC-type zinc finger specifically binds to unmethylated CpG dinucleotides, positioning the autoinhibitory linker between the DNA and the active site, thus providing a mechanism to ensure that only hemimethylated CpG dinucleotides undergo methylation

• Neuropathy, hereditary sensory, 1E (HSN1E)

  A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.

• Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (ADCADN)

  An autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy, cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression.