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FLASH GENE
Symbol DNMT1 contributors: shn/ - updated : 01-08-2010
HGNC name DNA (cytosine-5-)-methyltransferase 1
HGNC id 2976
Corresponding disease
HSANDHL hereditary sensory and autonomic neuropathy with dementia and hearing loss
Location 19p13.2      Physical location : 10.244.022 - 10.305.755
Synonym name
  • DNA methyltransferase 1
  • DNA (cytosine-5)-methyltransferase 1
  • DNA MTase HsaI
  • DNA methyltransferase HsaI
  • m.HsaI
  • CXXC finger protein 9
  • CXXC-type zinc finger protein 9
    • Synonym symbol(s) MCMT, DNMT, AIM, DNM1, CXXC9, FLJ16293, MGC104992
    EC.number 2.1.1.37
    DNA
    TYPE functioning gene
    STRUCTURE 61.73 kb     41 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • promoter is a TATA-less promoter and therefore its transcriptional activity is highly dependent on the binding of transcription factors to the basal promoter region
  • E2F-binding site located within the transcription initiation region is critical for the regulation of DNMT1 transcription in proliferating cells via the E2F1/pRB pathway
    • MAPPING cloned Y linked N status confirmed
    Map pter - D19S586 - D19S583 - DNMT1 - D19S584 - D19S906 - cen
    Physical map
    FLJ20079 19p13.2 hypothetical protein FLJ20079 LOC342969 19p13.2 similar to hypothetical protein MGC45408 LOC390887 19 similar to hypothetical protein MGC45408 LOC162993 19p13.2 hypothetical protein LOC162993 UBE2L4 19q13.1-q13.2 ubiquitin-conjugating enzyme E2L 4 FBXL12 19p13.2 F-box and leucine-rich repeat protein 12 PIN1 19p13.2 protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1 UBL5 19p13.3 ubiquitin-like 5 LOC390888 19 similar to 60S ribosomal protein L10 (QM protein homolog) OLFM2 19p13.2 olfactomedin 2 COL5A3 19p13.2 collagen, type V, alpha 3 RDH8 19p13.2-p13.3 retinol dehydrogenase 8 (all-trans) LOC388502 19 similar to Complement C3 precursor LOC388503 19 similar to Complement C3-1 LOC147740 19p13.2 similar to complement C3 protein (GPC3) precursor FLJ11286 19p13.2 hypothetical protein FLJ11286 ANGPTL6 19p13.2 angiopoietin-like 6 PPAN 19p13 peter pan homolog (Drosophila) P2RY11 19p13.2 purinergic receptor P2Y, G-protein coupled, 11 EIF3S4 19p13.2 eukaryotic translation initiation factor 3, subunit 4 delta, 44kDa DNMT1 19p13.2 DNA (cytosine-5-)-methyltransferase 1 EDG5 19p13.2 endothelial differentiation, sphingolipid G-protein-coupled receptor, 5 LOC388504 19 LOC388504 MRPL4 19p13.2 mitochondrial ribosomal protein L4 ICAM1 19p13.3-p13.2 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor ICAM4 19p13.2-cen intercellular adhesion molecule 4, Landsteiner-Wiener blood group ICAM5 19p13.2 intercellular adhesion molecule 5, telencephalin LOC388505 MGC19604 19p13.2 similar to RIKEN cDNA B230118G17 gene RAVER1 19p13.2 RAVER1 ICAM3 19p13.3-p13.2 intercellular adhesion molecule 3 TYK2 19p13.2 tyrosine kinase 2 CDC37 19p13.2 CDC37 cell division cycle 37 homolog (S. cerevisiae) PDE4A 19p13.2 phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homolog, Drosophila) KEAP1 19p13.2 kelch-like ECH-associated protein 1 EDG8 19p13.2 endothelial differentiation, sphingolipid G-protein-coupled receptor, 8 AUTL4 19p13.2 AUT-like 4, cysteine endopeptidase (S. cerevisiae) FLJ12949 19p13.2 hypothetical protein FLJ12949 CDKN2D 19p13.2 cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4) AP1M2 19p13.2 adaptor-related protein complex 1, mu 2 subunit CTL2 19p13.1 adaptor-related protein complex 1, mu 2 subunit
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    41 - 5425 183 1632 - 2010 20081831
    also called DNMT1a
    40 splicing 5377 - 1616 less expressed 2010 20081831
  • also called DNMT1f
  • insertion of 48bp from intron 4 becoming exon 5a
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver    
    Hearing/Equilibriumear   highly
    Lymphoid/Immunelymph node   predominantly
     thymus   moderately
    Nervousbrain    
    Reproductivefemale systemuteruscervix highly
     female systembreastmammary gland moderately
    Respiratorylung    
    Skin/Tegumentskin   highly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningepidermisstratum basalehighly
    Muscularstriatumskeletal  
    cell lineage expressed in epidermal progenitor-containing cell populations and is lost during differentiation
    cell lines abundantly, in cell lines
    fluid/secretion moderately in blood, highly in lymph
    at STAGE
    cell cycle     cell cycle, S
    Text reduced to non detectable levels at the G0 phase of the cell cycle and dramatically induced upon entrance into the S-phase of the cell cycle
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminal nuclear localization signal (NLS), replication foci-targeting sequences and interacting with several proteins such as DMAP1, HDAC2 (histone deacetylase), PCNA and RB
  • the zinc binding region with the cysteine-rich (CXXC) motif, that bound specifically to unmethylated CpG dinucleotides, encompassing the N-terminus region of DNMT1 and cooperating with the catalytic domain for DNA methyltransferase activity
  • two BAH domains
  • a bromodomain
  • a C terminal region with five conserved motifs involved in catalytic activities, alternatively spliced, DNMT catalytic domain
    • HOMOLOGY
    interspecies ortholog to DNMT1, Pan troglodytes
    ortholog to dnmt1, Danio rerio
    ortholog to Dnmt1, Rattus norvegicus
    ortholog to Dnmt1, Mus musculus
    Homologene
    FAMILY
  • C5-methyltransferase family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,nucleus,chromatin/chromosome,heterochromosome
    text
  • replication fork
  • binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix
    • basic FUNCTION
  • involved in the maintenance of DNA-methylation activities
  • required to maintain global methylation and aberrant CpG island methylation in cancers
  • playing a role in the mismatch repair gene
  • involved in the methylation maintenance transcription repression
  • acting as a putative mediator of the methylation process and cooperating with RB to repress transcription from promoters containing E2F binding sites
  • may be the enzyme primarily responsible for maintenance of the global methylation status of genomic DNA
  • contributing to the preservation of the correct organization of large heterochromatic regions
  • required for maintenance of bulk DNA methylation, and essential for maintenance of DNA methylation, proliferation, and survival of cancer cells
  • being responsible for maintaining methylation patterns established in development
  • regulates BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation
  • responsible for the aberrant hypermethylation of CpG islands and the silencing of tumor suppressor genes
  • crucial transcription regulator for DNMT1
  • maintains DNA methylation patterns after cellular replication, and essential for epidermal progenitor cell function
  • acting as a maintenance methyltransferase, playing an essential role in the faithful propagation of the genomic methylation profile from mother to daughter cells following cell division
  • may participate in sensing DNA damage, in one of the cell-cycle checkpoints, or in both
  • acting as a regulator of genome integrity and as an early responder to DNA DSBs
  • recruited early and transiently to DSBs by multiple DNA damage-related interactions and that it plays a role in modulating the cellular response to DNA damage
  • both DNMT1 and UHRF1 coprecipitate with ubiquitin specific peptidase 7 (USP7), a de-ubiquitinating enzyme
  • appears to be capable of both initiating and maintaining cytosine methylation in the nucleus, and the lack of de novo methyltransferases in mitochondria implicates mtDNMT1 in both processes in this organelle
  • most prevalent DNA methyltransferase found in cells and which is responsible for maintaining the DNA methylation patterns once formed
  • link between DNMT1 insufficiency and genomic instability
    • CELLULAR PROCESS nucleotide, chromatin organization, methylation
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development , immunity/defense
    PATHWAY
    metabolism
    signaling
    CDKN1A-EP300-DNMT1 pathway may play a pivotal role to ensure regulated DNMT1 expression and DNA methylation in mammalian cell division
    a component
  • complexing with RB1, E2E1, HDAC1 and BB1
  • also complexing with HDAC2, DMAP1
  • component of complexes containing SUV39H1
  • KAT5, UHRF1, HDAC1 and DNMT1 are present in the same macro-molecular complex and are partners for the epigenetic code inheritance
    • INTERACTION
    DNA
  • interaction of mtDNMT1 with mtDNA is potentially proportional to CpG density, supporting a functional role for mtDNMT1 in establishment and maintenance of mtDNA methylation
    • RNA
    small molecule
    protein
  • proliferating cell nuclear antigen, PCNA
  • MBD2 and MBD3
  • HDAC1 and E2F1
  • cooperating with DNMT3A for de novo methylation of DNA
  • STAT3 and HDAC1 for epigenetic silencing of PTPN6 in various tumors
  • histone deacetylase 2, HDAC2 and DNA methyltransferase 1 associated protein 1, DMAP1
  • DNMT3a and DNMT3b
  • retinoblastoma protein, RB
  • SUV39H1 histone methyltransferase
  • methyl CpG binding protein 2, MECP2
  • regulator of G-protein signaling 6, RGS6
  • HESX1
  • CXXC finger 1 (PHD domain), CXXC1
  • SRA domain of SRA domain of ICBP90
  • AOF2 (demethylates and stabilizes DNMT1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems)
  • UHRF1 through SET and RING finger-associated (SRA) domain
  • SETD7 regulates DNA methyltransferase-1 (DNMT1) activity in mammalian cells by promoting degradation of DNMT1 and thus allows epigenetic changes via DNA demethylation
  • binding of CDK5 to the N-terminal domain of DNMT1
  • USP7 is an interaction partner of DNMT1 and UHRF1
  • operates either as a functional intermediary or in cooperation with E2F1 inhibiting AR gene expression in a methylation independent manner
    • cell & other
    REGULATION
    activated by DMAP1 (activates DNMT1 preferentially at sites of homologous recombination repair)
    Phosphorylated by CDKs at Ser154 whichis important for enzymatic activity and protein stability of DNMT1
    Other SUMOylated which significantly enhances its methylase activity
    regulation through modifications mediated by AKT1 and SETD7, that affects cellular DNMT1 levels
    ASSOCIATED DISORDERS
    corresponding disease(s) HSANDHL
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in telencephalic GABAergic interneurons of schizophrenia brain
    tumoral       gain of function
    in leukemia
    constitutional     --low  
    by specific hypermethylation in placenta, and promoter methylation attenuates transcriptional activity in trophoblast cells
    tumoral     --low  
    responsible for induction of DDX53 drug-resistant cancer cells
    constitutional        
    affect the DNA damage response (DDR) in the cell
    Susceptibility to autoimmune disease
    Variant & Polymorphism SNP increasing the risk of autoimmune disease
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    development of novel combination therapies that will exploit DNMT1 role not only as a maintenance methyltransferase, but also as a modulator of the DNA damage response, to more efficiently target tumor cells for destruction
    ANIMAL & CELL MODELS
  • Dnmt1 mutant mice with 90% of hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on are viable but display severe neuronal cell death between E14.5
  • conditional mutant mice lacking Dnmt1 and Dnmt3 in forebrain excitatory neurons have abnormal long-term plasticity in the hippocampal CA1 region with deficits in learning and memory