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

2008-03-01   Eri Arai , Yae Kanai 

Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.


Atlas Image



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.


CDS 4851bp. 40 exons.


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.



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.
Atlas Image
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.


AA; 1616.EC number; Estimated molecular weight 183035Dt.


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.


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.


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.


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.



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.


Involvement of germline mutation of the DNMT1 gene in human diseases has not yet been clarified.


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 name
Intestinal adenomas
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 name
Precancerous conditions and cancers associated with chronic inflammation and/or persistent infection with viruses
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 name
Urinary bladder cancers
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 name
Ductal carcinomas of the pancreas
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.
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.
Atlas Image
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.


Pubmed IDLast YearTitleAuthors
164910702006Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?Baylin SB et al
32102461988Cloning 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 et al
127242092003Unanswered questions about the role of promoter methylation in carcinogenesis.Bestor TH et al
127028682003Chromosomal instability and tumors promoted by DNA hypomethylation.Eden A et al
147422722004Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers.Etoh T et al
155261632004Biochemistry and biology of mammalian DNA methyltransferases.Hermann A et al
176212732008Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice.Howard G et al
127242262003Epigenetics in carcinogenesis and cancer prevention.Jones PA et al
178932342007Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state.Kanai Y et al
126371552003Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers.Kanai Y et al
75376361995Suppression of intestinal neoplasia by DNA hypomethylation.Laird PW et al
126716642003The power and the promise of DNA methylation markers.Laird PW et al
16066151992Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Li E et al
122091412002Chromatin modification and epigenetic reprogramming in mammalian development.Li E et al
146344512003Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder.Nakagawa T et al
165375622006DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas.Peng DF et al
127124452003Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas.Saito Y et al
171967392007Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion.Sawada M et al
89175201996Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene.Tucker KL et al
157190302005Detection and interpretation of altered methylation patterns in cancer cells.Ushijima T et al
15944471992Isolation and characterization of the cDNA encoding human DNA methyltransferase.Yen RW et al

Other Information

Locus ID:

NCBI: 1786
MIM: 126375
HGNC: 2976
Ensembl: ENSG00000130816


dbSNP: 1786
ClinVar: 1786
TCGA: ENSG00000130816


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cysteine and methionine metabolismKEGGko00270
Cysteine and methionine metabolismKEGGhsa00270
Metabolic pathwaysKEGGhsa01100
Methionine degradationKEGGhsa_M00035
Methionine degradationKEGGM00035
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Gene ExpressionREACTOMER-HSA-74160
Epigenetic regulation of gene expressionREACTOMER-HSA-212165
PRC2 methylates histones and DNAREACTOMER-HSA-212300
Negative epigenetic regulation of rRNA expressionREACTOMER-HSA-5250941
NoRC negatively regulates rRNA expressionREACTOMER-HSA-427413
DNA methylationREACTOMER-HSA-5334118

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
176736202007UHRF1 plays a role in maintaining DNA methylation in mammalian cells.449
119327492002DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.393
202288042010Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.364
192119352009MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1.293
170854822006Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication.208
241079922013DNMT1-interacting RNAs block gene-specific DNA methylation.188
124967602003DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells.171
213212012011DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria.165
118348372002Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.164
200818312010DNMT1 maintains progenitor function in self-renewing somatic tissue.163


Eri Arai ; Yae Kanai

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

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

Online version: http://atlasgeneticsoncology.org/gene/40347/dnmt1-(dna-(cytosine-5-)-methyltransferase-1))