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DNMT1 (DNA (cytosine-5-)-methyltransferase 1))

Identity

Other namesAIM
DNMT
DNA
MCMT
FLJ16293
CXXC9
HGNC (Hugo) DNMT1
LocusID (NCBI) 1786
Location 19p13.2
Location_base_pair Starts at 10244022 and ends at 10305755 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
Note DNA methylation, a covalent chemical modification resulting in addition of a methyl (CH3) group at the carbon 5 position of the cytosine ring in CpG dinucleotides, plays important roles in chromatin structure modulation, transcriptional regulation and genomic stability, and is essential for the development of mammals. Aberrant DNA methylation is associated with multistage human carcinogenesis and developmental abnormalities.
Until the identification of DNA methyltransferase 2 (DNMT2), DNMT3a and DNMT3b in 1998, DNMT1 (EC2.1.1.37) had been the only known DNMT, and is currently the major and best known of this enzyme family.
Dnmt1 (-/-) mouse embryos are stunted, show delayed development, and do not survive past mid-gestation (Li E et al. 1992).
The carboxy-terminal catalytic domain of DNMTs transfers methyl groups from S-adenosyl-L-methionine (AdoMet) to cytosines. The preference of DNMT1 for hemimethylated over unmethylated substrates in vitro and its targeting of replication foci are believed to allow copying of the methylation pattern of the parental strand to the newly synthesized daughter DNA strand. Thus, DNMT1 has been recognized as the "maintenance" DNMT, whereas DNMT3a and DNMT3b do show de novo DNA methylation activity in vitro. On the other hand, since de novo methylation of CpG islands has actually been observed in human fibroblasts overexpressing DNMT1, DNMT1 is capable of de novo DNA methylating activity in vivo as well as having a maintenance function. DNMT1 can interact with numerous proteins, such as DNMT1-associated protein (DMAP) 1, histone deacetylase (HDAC) 1, HDAC2, and Rb, and can repress gene transcription.

DNA/RNA

Note Bestor T et al. (1988) cloned murine Dnmt cDNA and found that its C-terminal domain of 570 amino acid residues showed striking similarities to a catalytic methyltransferase domain of bacterial type II DNA cytosine methyltransferases. Yen RW et al. (1992) isolated overlapping cDNA clones encoding a transcript for human DNMT. Tucker KL et al. (1996) clarified that an N-terminal domain of mammalian DNMT is crucial for stable expression and function in vivo. Human DNMT1 mRNA consists of 40 exons.
Description CDS 4851bp. 40 exons.
Transcription DNMT1 has different translational start points, and exists as different splice variants. The predominant splicing isoform in human somatic cells comprises.
1616 amino acid residues. A shorter germ-cell-specific form of DNMT1 known as DNMT1o is found in growing oocytes and during embryonic preimplantation development. Human DNMT1o exon 1 lies 6 kb upstream of the somatic exon 1 and splices onto exon 2. The predicted translation initiation site for the oocyte-specific mRNA is further downstream in exon 4. The intrinsic stability of the DNMT1o protein allows the creation of stable ooplasmic stores of DNMT1o. Another splice form of DNMT1 is DNMT1b, which incorporates an additional 48 in-frame nucleotides between exons 4 and 5. The amount of DNMT1b protein in somatic cells is very small and its biological functions are still unclear.

Protein

Note The structure of DNMT1 indicates that the DNMT1 gene could have been formed during the fusion of a prokaryotic DNMT gene with a mammalian DNA binding protein gene. The N-terminal regulatory domain of DNMT1 is essential for discrimination between hemimethylated and unmethylated DNA strands and contains a proliferating cell nuclear antigen-binding domain (PBD), a nuclear localization signal (NLS), an cysteine-rich ATRX zinc finger DNA-binding motif and a polybromo homology domain (PHD) targeting DNMT1 to the replication foci. Thus DNMT1 forms the core of the DNA replication machinery complex.
The charge-rich motif of the N-terminal domain of DNMT1 interacts with DMAP1 and represses transcription without the participation of HDACs. The DNMT1 N-terminal domain can also interact with E2F1 transcription factor, HDAC1 and HDAC2. In addition, DNMT1 interacts with methyl CpG binding proteins such as MBD2, MBD3 and MeCPs. Thus DNMT1 is also a crucial element of the transcription suppression complex.
The C-terminal catalytic domain of DNMT1 is characterized by the presence of 5 conserved amino acid motifs, namely I, IV, VI, IX and X. Motifs I and X are filed together to form most of the binding site for AdoMet as the source of the methyl group. Motif IV contains the prolylcysteinyl dipeptide that provides the thiolate at the active site. Motif VI contains the glutamyl residue that protonates the 3 position of the target cytosine. Motif IX has a role in maintaining the structure of the target recognition domain, which is usually located between motifs VIII and IX.
 
  A: Structure of mammalian DNMT1 protein. Charge-rich region, the site of interaction with DMAP1; PBD, proliferating cell nuclear antigen-binding domain; NLS, nuclear localization signal; cysteine-rich ATRX, zinc finger DNA-binding motif; PHD-like, polybromo homology domain targeting DNMT1 to the replication foci. I, IV, VI, IX and X are conserved motifs of the C-terminal catalytic domain of DNMTs.
B: Homology.
Description AA; 1616.EC number; 2.1.1.37. Estimated molecular weight 183035Dt.
Expression Although DNMT1 is down-regulated in growth-arrested somatic cells, its expression level during the cell cycle is nearly constant. It shows nucleoplasmic expression during G1 and G2 phases, but is associated with replication foci during S-phase. DNMT1o is found in growing oocytes.
Localisation DNMT1 is localized to nuclei of somatic cells and is targeted to replication foci during S-phase, whereas it is actively excluded from the nuclei in fertilized eggs and stored in the cytoplasm, leading to so-called passive demethylation during the first DNA replication cycles of fertilized eggs.
Function DNMT1 uses AdoMet as the source of the methyl group being transferred to the DNA bases. DNMTs pull their target base out of the DNA helix prior to methylation, a process called base flipping. A key feature of the catalytic process is a nucleophilic attack by the thiol group of the cysteine residue in conserved motif IV on the carbon-6 of the target cytosine. The formation of the covalent bond activates the C5 atom towards electrophilic attack and leads to addition of the methyl group to carbon-5 of the cytosine followed by elimination of the 5-position proton and resolution of the covalent intermediate. The glutamic acid of motif VI is important for stabilizing the DNA protein complex. In addition to methyltransferase activity, through interaction with numerous proteins, such as DMAP1, E2F1, HDAC1, HDAC2 and methyl CpG binding proteins, DNMT1 becomes a crucial element of the transcription suppression complex.
Homology Homologs of DNMT1 have been found in nearly all eukaryotes whose DNA bears 5-methylcytosine, but not in those that lack it. Although DNMT2 contains the full set of conserved motifs of the catalytic domain, it lacks the N-terminal domain characteristic of eukaryotic DNMTs. The methyltransferase activity of the recombinant DNMT2 protein is weak in vitro and in vivo, and the biological function of DNMT2 is still unclear. The N-terminal regions of DNMT3A and DNMT3B are highly divergent on the N-terminal side of the Cys-rich region but their C-terminal regions are more closely related to the multispecific DNMTs encoded by phages of the Bacillus species than to the DNMT1 or DNMT2 families. DNMT3L lacks conserved motifs of the catalytic domain but is otherwise closely related to the C-terminal domain of DNMT3A and DNMT3B.

Mutations

Note The frequency of somatic mutation of the DNMT1 gene is generally low in human cancers, and DNMT1 gene mutation that can potentially cause a genome-wide alteration of DNA methylation status may be a rare event during human carcinogenesis.
Germinal Involvement of germline mutation of the DNMT1 gene in human diseases has not yet been clarified.
Somatic A study employing polymerase chain reaction-single strand conformation polymorphism analysis of all 40 coding exons revealed mutations in coding exons of the DNMT1 gene in 7% of colorectal cancers: they consisted of a one-base deletion resulting in deletion of the whole catalytic domain, and a point mutation resulting in a single amino acid substitution. No stomach cancers or hepatocellular carcinomas (HCCs) showed mutations in the coding exons of the DNMT1 gene. No mutation in the 5'-flanking region of the DNMT1 gene was detected in any of the examined colorectal and stomach cancers or HCCs.

Implicated in

Entity Intestinal adenomas
Note Human cancers generally show global DNA hypomethylation accompanied by region-specific hypermethylation. A reduction of DNMT1 activity in ApcMin mice due to heterozygosity of the Dnmt1 gene, in conjunction with treatment using the DNA methyltransferase inhibitor 5-aza-deoxycytidine, reduced the average number of intestinal adenomas (Laird PW et al., 1995). On the other hand, genomic hypomethylation in Nf1+/ p53+/ (NPcis) mice due to introduction of a hypomorphic allele of Dnmt 1 (Dnmt1Chip/) induced sarcomas at an earlier age compared with NPcis littermates possessing normal levels of DNA methylation (Dnmt1Chip/+) (Eden et al., 2003). The loss of heterozygosity (LOH) rate was increased in hypomethylated cells in Dnmt1Chip/- mice. One of the proposed roles of DNA methylation is suppression of transposable elements in mammalian cells, and chromosomal instability events accompanied by activation of endogenous retroviral elements was also observed in Dnmt1Chip/- mice (Howard et al., 2008).
  
Entity Precancerous conditions and cancers associated with chronic inflammation and/or persistent infection with viruses
Note Examination of clinical tissue samples showed that overexpression of DNMT1 is frequent in precancerous conditions and cancers associated with chronic inflammation and/or persistent infection with viruses or other pathogenic microorganisms, such as hepatitis B or C viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV). DNMT1 mRNA levels were significantly higher even in non-cancerous liver tissues showing chronic hepatitis or cirrhosis, which are considered to be precancerous conditions of HCC, than in normal liver tissues, and were even higher in HCCs. EBV infection in stomach cancers is significantly associated with marked accumulation of DNA hypermethylation in C-type CpG islands that are usually methylated in a cancer-specific (not age-dependent) manner. Induction of latent membrane protein 1 of EBV has been reported to induce DNMT1 overexpression in cultured cancer cells. Cervical intraepithelial neoplasia (CIN) is a precursor lesion for squamous cell carcinoma of the uterine cervix closely associated with HPV infection. DNMT1 protein expression is increased even in low-grade CINs compared to normal squamous epithelium, and further increased in higher-grade CINs and squamous cell carcinomas of the uterine cevix. HPV-16 E7 protein has been reported to associate directly with DNMT1 and stimulate the methyltransferase activity of DNMT1 in vitro.
  
Entity Urinary bladder cancers
Note Even non-cancerous urothelia showing no remarkable histological features obtained from patients with urinary bladder cancers can be considered precancerous, because they may be exposed to carcinogens in the urine. It has been debatable whether increased DNMT1 expression in cancers is due to an increase in the proportion of dividing cells or to an acute increase of DNMT1 expression per individual cancer cell. However, the incidence of nuclear DNMT1 immunoreactivity had already increased independently of cell proliferative activity in non-cancerous urothelia showing no marked histological features obtained from patients with urinary bladder cancers, where the PCNA labeling index had not yet increased, compared to that in normal urothelia obtained from patients without urinary bladder cancers. DNMT1 overexpression was not a secondary effect of increased cell proliferative activity but preceded increased cell proliferative activity during multistage urothelial carcinogenesis.
  
Entity Ductal carcinomas of the pancreas
Note Ductal carcinomas frequently emerge in pancreases damaged by chronic pancreatitis. Therefore, at least a proportion of peripheral pancreatic duct epithelia with an inflammatory background may be at the precancerous stage. The incidence of nuclear DNMT1 immunoreactivity was significantly elevated in peripheral pancreatic ductal epithelia with an inflammatory background and pancreatic intraepithelial neoplasia (PanIN) as a precancerous lesion than in peripheral pancreatic ductal epithelia without an inflammatory background. The incidence of nuclear DNMT1 immunoreactivity was significantly associated with the degree of PanIN dysplasia. The incidence of nuclear DNMT1 immunoreactivity was significantly higher in invasive ductal carcinomas of the pancreas than in PanINs. The average number of methylated tumor-related genes in microdissected specimens of ductal carcinomas of the pancreas was significantly correlated with the expression level of DNMT1 protein examined immunohistochemically in the precisely microdissected areas. CpG island methylator phenotype (CIMP) is defined as frequent DNA hypermethylation of C-type CpG islands. The levels of DNMT1 expression were significantly higher in CIMP-positive colorectal and stomach cancers than in CIMP-negative colorectal and stomach cancers, but no such association was observed for the expression of DNMT2, DNMT3a or DNMT3b. Thus DNMT1 may be responsible for de novo methylation of CpG islands during multistage carcinogenesis. A theoretical explanation for the role of DNMT1 in de novo DNA methylation in human cancers with dysfunction of p21WAF1, which competes with DNMT1 for binding with PCNA, has been proposed. Moreover, it has recently been suggested that DNMT1 is capable of de novo DNA methylation activity in vivo as well as having a maintenance function: de novo methylation of CpG islands has actually been observed in human fibroblasts overexpressing DNMT1. Therefore, it is feasible that, in cancers, DNMT1 overexpression participates in regional DNA hypermethylation.
Prognosis The incidence of increased DNMT1 protein expression in HCCs is significantly correlated with poorer tumor differentiation and portal vein involvement. Moreover, the recurrence-free and overall survival rates of patients with HCCs showing increased DNMT1 protein expression are significantly lower than those of patients with HCCs that do not. Increased DNMT1 protein expression in ductal carcinomas of the pancreas is significantly correlated with the extent of cancer invasion to the anterior pancreatic capsule, retroperitoneal tissue and other surrounding organs, and with advanced stage, suggesting that DNMT1 overexpression is associated with aggressiveness of pancreatic cancers. Moreover, patients with ductal carcinomas of the pancreas showing increased DNMT1 protein expression have a poorer prognosis.
 
Immunohistochemistry for DNMT1 in pancreatic cancer.
Nuclear DNMT1 immunoreactivity was observed in invasive ductal carcinoma cells of the pancreas. * lymphocytes as internal positive controls. Original magnification x20.
  

External links

Nomenclature
HGNC (Hugo)DNMT1   2976
Cards
AtlasDNMT1ID40347ch19p13
Entrez_Gene (NCBI)DNMT1  1786  DNA (cytosine-5-)-methyltransferase 1
GeneCards (Weizmann)DNMT1
Ensembl (Hinxton)ENSG00000130816 [Gene_View]  chr19:10244022-10305755 [Contig_View]  DNMT1 [Vega]
AceView (NCBI)DNMT1
Genatlas (Paris)DNMT1
WikiGenes1786
SOURCE (Princeton)NM_001130823 NM_001379
Genomic and cartography
GoldenPath (UCSC)DNMT1  -  19p13.2   chr19:10244022-10305755 -  19p13.2   [Description]    (hg19-Feb_2009)
EnsemblDNMT1 - 19p13.2 [CytoView]
Mapping of homologs : NCBIDNMT1 [Mapview]
OMIM126375   614116   
Gene and transcription
Genbank (Entrez)AB209413 AF180682 AK122759 AY927518 BC092517
RefSeq transcript (Entrez)NM_001130823 NM_001379
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_028016 NT_011295 NW_001838483 NW_004929414
Consensus coding sequences : CCDS (NCBI)DNMT1
Cluster EST : UnigeneHs.202672 [ NCBI ]
CGAP (NCI)Hs.202672
Alternative Splicing : Fast-db (Paris)GSHG0015490
Alternative Splicing GalleryENSG00000130816
Gene ExpressionDNMT1 [ NCBI-GEO ]     DNMT1 [ SEEK ]   DNMT1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP26358 (Uniprot)
NextProtP26358  [Medical]
With graphics : InterProP26358
Splice isoforms : SwissVarP26358 (Swissvar)
Catalytic activity : Enzyme2.1.1.37 [ Enzyme-Expasy ]   2.1.1.372.1.1.37 [ IntEnz-EBI ]   2.1.1.37 [ BRENDA ]   2.1.1.37 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)BAH (PS51038)    C5_MTASE_1 (PS00094)    C5_MTASE_2 (PS00095)    SAM_MT_C5 (PS51679)    ZF_CXXC (PS51058)   
Domains : Interpro (EBI)BAH_dom    C5_DNA_meth_AS    C5_MeTfrase    Cytosine_MeTrfase1_RFD    DMAP1-bd    DNA_C5-MeTrfase_1_euk    Znf_CXXC   
Related proteins : CluSTrP26358
Domain families : Pfam (Sanger)BAH (PF01426)    DMAP_binding (PF06464)    DNA_methylase (PF00145)    DNMT1-RFD (PF12047)    zf-CXXC (PF02008)   
Domain families : Pfam (NCBI)pfam01426    pfam06464    pfam00145    pfam12047    pfam02008   
Domain families : Smart (EMBL)BAH (SM00439)  
DMDM Disease mutations1786
Blocks (Seattle)P26358
PDB (SRS)3EPZ    3PTA    3SWR   
PDB (PDBSum)3EPZ    3PTA    3SWR   
PDB (IMB)3EPZ    3PTA    3SWR   
PDB (RSDB)3EPZ    3PTA    3SWR   
Human Protein AtlasENSG00000130816
Peptide AtlasP26358
HPRD00532
IPIIPI00031519   IPI00220918   IPI00220919   IPI01011182   
Protein Interaction databases
DIP (DOE-UCLA)P26358
IntAct (EBI)P26358
FunCoupENSG00000130816
BioGRIDDNMT1
InParanoidP26358
Interologous Interaction database P26358
IntegromeDBDNMT1
STRING (EMBL)DNMT1
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  DNA binding  RNA binding  DNA (cytosine-5-)-methyltransferase activity  protein binding  nucleus  replication fork  centromeric heterochromatin  DNA methylation  transcription, DNA-templated  transcription factor binding  zinc ion binding  methyl-CpG binding  DNA-methyltransferase activity  maintenance of DNA methylation  positive regulation of gene expression  gene silencing  chromatin modification  regulation of cell proliferation  positive regulation of histone H3-K4 methylation  negative regulation of histone H3-K9 methylation  cellular response to amino acid stimulus  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  DNA binding  RNA binding  DNA (cytosine-5-)-methyltransferase activity  protein binding  nucleus  replication fork  centromeric heterochromatin  DNA methylation  transcription, DNA-templated  transcription factor binding  zinc ion binding  methyl-CpG binding  DNA-methyltransferase activity  maintenance of DNA methylation  positive regulation of gene expression  gene silencing  chromatin modification  regulation of cell proliferation  positive regulation of histone H3-K4 methylation  negative regulation of histone H3-K9 methylation  cellular response to amino acid stimulus  
Pathways : KEGGCysteine and methionine metabolism    MicroRNAs in cancer   
REACTOMEDNMT1
Protein Interaction DatabaseDNMT1
Wikipedia pathwaysDNMT1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)DNMT1
SNP (GeneSNP Utah)DNMT1
SNP : HGBaseDNMT1
Genetic variants : HAPMAPDNMT1
1000_GenomesDNMT1 
ICGC programENSG00000130816 
Somatic Mutations in Cancer : COSMICDNMT1 
CONAN: Copy Number AnalysisDNMT1 
Mutations and Diseases : HGMDDNMT1
OMIM126375    614116   
GENETestsDNMT1
Disease Genetic AssociationDNMT1
Huge Navigator DNMT1 [HugePedia]  DNMT1 [HugeCancerGEM]
Genomic VariantsDNMT1  DNMT1 [DGVbeta]
Exome VariantDNMT1
dbVarDNMT1
ClinVarDNMT1
snp3D : Map Gene to Disease1786
General knowledge
Homologs : HomoloGeneDNMT1
Homology/Alignments : Family Browser (UCSC)DNMT1
Phylogenetic Trees/Animal Genes : TreeFamDNMT1
Chemical/Protein Interactions : CTD1786
Chemical/Pharm GKB GenePA27443
Clinical trialDNMT1
Cancer Resource (Charite)ENSG00000130816
Other databases
Probes
Litterature
PubMed306 Pubmed reference(s) in Entrez
CoreMineDNMT1
iHOPDNMT1

Bibliography

Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases.
Bestor T, Laudano A, Mattaliano R, Ingram V.
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PMID 3210246
 
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Contributor(s)

Written03-2008Eri Arai, Yae Kanai
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.

Citation

This paper should be referenced as such :
Arai E, Kanai Y . DNMT1 (DNA (cytosine-5-)-methyltransferase 1)). Atlas Genet Cytogenet Oncol Haematol. March 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/DNMT1ID40347ch19p13.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44376/1/03-2008-DNMT1ID40347ch19p13.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:24:36 CEST 2014

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