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

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

Identity

Other names AIM

DNMT

DNA

MCMT

FLJ16293

CXXC9

Hugo DNMT1

Location 19p13.2

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

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.

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.

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
Hugo DNMT1

GDB DNMT1

Entrez_Gene DNMT1  1786  DNA (cytosine-5-)-methyltransferase 1

Cards
Atlas DNMT1ID40347ch19p13

GeneCards DNMT1

Ensembl DNMT1 [Search_View]   ENSG00000130816 [Gene_View]

Genatlas DNMT1
GeneLynx DNMT1

eGenome DNMT1

euGene 1786

Genomic and cartography
GoldenPath DNMT1 - 19p13.2   chr19:10105023-10166811 - 19p13.2   [Description]    (hg18-Mar_2006)

Ensembl DNMT1 - 19p13.2 [CytoView]
NCBI Mapview

OMIM Disease map [OMIM]

HomoloGene DNMT1

Gene and transcription
Genbank AB209413 [ ENTREZ ]

Genbank AF180682 [ ENTREZ ]

Genbank AK122759 [ ENTREZ ]

Genbank AY927518 [ ENTREZ ]

Genbank BC092517 [ ENTREZ ]

RefSeq NM_001379 [ SRS ]    NM_001379 [ ENTREZ ]

RefSeq AC_000062 [ SRS ]    AC_000062 [ ENTREZ ]

RefSeq AC_000151 [ SRS ]    AC_000151 [ ENTREZ ]

RefSeq NC_000019 [ SRS ]    NC_000019 [ ENTREZ ]

RefSeq NT_011295 [ SRS ]    NT_011295 [ ENTREZ ]

RefSeq NW_001838483 [ SRS ]    NW_001838483 [ ENTREZ ]

RefSeq NW_927195 [ SRS ]    NW_927195 [ ENTREZ ]

AceView DNMT1 AceView - NCBI

Unigene Hs.202672 [ SRS ]    Hs.202672 [ NCBI ]     HS202672 [ spliceNest ]

Fast-db 5972 (alternative variants)

Protein : pattern, domain, 3D structure
SwissProt P26358 [ SRS]    P26358 [ EXPASY ]     P26358 [ INTERPRO ]

Prosite PS51038 BAH [ SRS ]    PS51038 BAH [ Expasy ]

Prosite PS00094 C5_MTASE_1 [ SRS ]    PS00094 C5_MTASE_1 [ Expasy ]

Prosite PS00095 C5_MTASE_2 [ SRS ]    PS00095 C5_MTASE_2 [ Expasy ]

Prosite PS51058 ZF_CXXC [ SRS ]    PS51058 ZF_CXXC [ Expasy ]

Interpro IPR001025 BAH [ SRS ]    IPR001025 BAH [ EBI ]

Interpro IPR001525 C5_DNA_meth [ SRS ]    IPR001525 C5_DNA_meth [ EBI ]

Interpro IPR010506 DMAP1_bd [ SRS ]    IPR010506 DMAP1_bd [ EBI ]

Interpro IPR017198 DNA_C5-MeTrfase_1 [ SRS ]    IPR017198 DNA_C5-MeTrfase_1 [ EBI ]

Interpro IPR002857 Znf_CXXC [ SRS ]    IPR002857 Znf_CXXC [ EBI ]

CluSTr P26358

Pfam PF01426 BAH [ SRS ]    PF01426 BAH [ Sanger ]    pfam01426 [ NCBI-CDD ]

Pfam PF06464 DMAP_binding [ SRS ]    PF06464 DMAP_binding [ Sanger ]    pfam06464 [ NCBI-CDD ]

Pfam PF00145 DNA_methylase [ SRS ]    PF00145 DNA_methylase [ Sanger ]    pfam00145 [ NCBI-CDD ]

Pfam PF02008 zf-CXXC [ SRS ]    PF02008 zf-CXXC [ Sanger ]    pfam02008 [ NCBI-CDD ]

Smart SM00439 BAH [EMBL]

Blocks P26358

PDB DNMT1 [ SRS ]    DNMT1 [ PdbSum ],   DNMT1 [ IMB ]   DNMT1 [ RSDB ]

HPRD 00532

Protein Interaction databases
DIP P26358
IntAct P26358
Polymorphism : SNP, mutations, diseases
OMIM 126375    [ map ]

GENECLINICS 126375

SNP DNMT1 [dbSNP-NCBI]

SNP NM_001379 [SNP-NCI]
SNP DNMT1 [GeneSNPs - Utah]  DNMT1] [HGBASE - SRS]

HAPMAP DNMT1 [HAPMAP]

COSMIC DNMT1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD DNMT1

General knowledge
Family Browser DNMT1 [UCSC Family Browser]

SOURCE NM_001379

SMD Hs.202672

SAGE Hs.202672

Enzyme 2.1.1.37 [ Enzyme-Expasy ]   2.1.1.37 [ Enzyme-SRS ]   2.1.1.37 [ IntEnz-EBI ]   2.1.1.37 [ BRENDA ]   2.1.1.37 [ KEGG ]   2.1.1.37 [ WIT ]

GO negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter

GO heterochromatin [Amigo]  heterochromatin

GO DNA binding [Amigo]  DNA binding

GO DNA (cytosine-5-)-methyltransferase activity [Amigo]  DNA (cytosine-5-)-methyltransferase activity

GO nucleus [Amigo]  nucleus

GO replication fork [Amigo]  replication fork

GO DNA methylation [Amigo]  DNA methylation

GO transcription [Amigo]  transcription

GO transcription factor binding [Amigo]  transcription factor binding

GO methyltransferase activity [Amigo]  methyltransferase activity

GO zinc ion binding [Amigo]  zinc ion binding

GO gene silencing [Amigo]  gene silencing

GO transcription repressor activity [Amigo]  transcription repressor activity

GO transferase activity [Amigo]  transferase activity

GO metal ion binding [Amigo]  metal ion binding

KEGG Methionine metabolism

PubGene DNMT1

TreeFam DNMT1

CTD 1786 [Comparative ToxicoGenomics Database]

Other databases
Probes
Probe DNMT1 Related clones (RZPD - Berlin)

PubMed
PubMed 114 Pubmed reference(s) in LocusLink

	Nomenclature
Hugo	DNMT1
GDB	DNMT1
Entrez_Gene	DNMT1 1786 DNA (cytosine-5-)-methyltransferase 1
	Cards
Atlas	DNMT1ID40347ch19p13
GeneCards	DNMT1
Ensembl	DNMT1 [Search_View] ENSG00000130816 [Gene_View]
Genatlas	DNMT1
GeneLynx	DNMT1
eGenome	DNMT1
euGene	1786
	Genomic and cartography
GoldenPath	DNMT1 - 19p13.2 chr19:10105023-10166811 - 19p13.2 [Description] (hg18-Mar_2006)
Ensembl	DNMT1 - 19p13.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	DNMT1
	Gene and transcription
Genbank	AB209413 [ ENTREZ ]
Genbank	AF180682 [ ENTREZ ]
Genbank	AK122759 [ ENTREZ ]
Genbank	AY927518 [ ENTREZ ]
Genbank	BC092517 [ ENTREZ ]
RefSeq	NM_001379 [ SRS ] NM_001379 [ ENTREZ ]
RefSeq	AC_000062 [ SRS ] AC_000062 [ ENTREZ ]
RefSeq	AC_000151 [ SRS ] AC_000151 [ ENTREZ ]
RefSeq	NC_000019 [ SRS ] NC_000019 [ ENTREZ ]
RefSeq	NT_011295 [ SRS ] NT_011295 [ ENTREZ ]
RefSeq	NW_001838483 [ SRS ] NW_001838483 [ ENTREZ ]
RefSeq	NW_927195 [ SRS ] NW_927195 [ ENTREZ ]
AceView	DNMT1 AceView - NCBI
Unigene	Hs.202672 [ SRS ] Hs.202672 [ NCBI ] HS202672 [ spliceNest ]
Fast-db	5972 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P26358 [ SRS] P26358 [ EXPASY ] P26358 [ INTERPRO ]
Prosite	PS51038 BAH [ SRS ] PS51038 BAH [ Expasy ]
Prosite	PS00094 C5_MTASE_1 [ SRS ] PS00094 C5_MTASE_1 [ Expasy ]
Prosite	PS00095 C5_MTASE_2 [ SRS ] PS00095 C5_MTASE_2 [ Expasy ]
Prosite	PS51058 ZF_CXXC [ SRS ] PS51058 ZF_CXXC [ Expasy ]
Interpro	IPR001025 BAH [ SRS ] IPR001025 BAH [ EBI ]
Interpro	IPR001525 C5_DNA_meth [ SRS ] IPR001525 C5_DNA_meth [ EBI ]
Interpro	IPR010506 DMAP1_bd [ SRS ] IPR010506 DMAP1_bd [ EBI ]
Interpro	IPR017198 DNA_C5-MeTrfase_1 [ SRS ] IPR017198 DNA_C5-MeTrfase_1 [ EBI ]
Interpro	IPR002857 Znf_CXXC [ SRS ] IPR002857 Znf_CXXC [ EBI ]
CluSTr	P26358
Pfam	PF01426 BAH [ SRS ] PF01426 BAH [ Sanger ] pfam01426 [ NCBI-CDD ]
Pfam	PF06464 DMAP_binding [ SRS ] PF06464 DMAP_binding [ Sanger ] pfam06464 [ NCBI-CDD ]
Pfam	PF00145 DNA_methylase [ SRS ] PF00145 DNA_methylase [ Sanger ] pfam00145 [ NCBI-CDD ]
Pfam	PF02008 zf-CXXC [ SRS ] PF02008 zf-CXXC [ Sanger ] pfam02008 [ NCBI-CDD ]
Smart	SM00439 BAH [EMBL]
Blocks	P26358
PDB	DNMT1 [ SRS ] DNMT1 [ PdbSum ], DNMT1 [ IMB ] DNMT1 [ RSDB ]
HPRD	00532
	Protein Interaction databases
DIP	P26358
IntAct	P26358
	Polymorphism : SNP, mutations, diseases
OMIM	126375 [ map ]
GENECLINICS	126375
SNP	DNMT1 [dbSNP-NCBI]
SNP	NM_001379 [SNP-NCI]
SNP	DNMT1 [GeneSNPs - Utah] DNMT1] [HGBASE - SRS]
HAPMAP	DNMT1 [HAPMAP]
COSMIC	DNMT1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	DNMT1
	General knowledge
Family Browser	DNMT1 [UCSC Family Browser]
SOURCE	NM_001379
SMD	Hs.202672
SAGE	Hs.202672
Enzyme	2.1.1.37 [ Enzyme-Expasy ] 2.1.1.37 [ Enzyme-SRS ] 2.1.1.37 [ IntEnz-EBI ] 2.1.1.37 [ BRENDA ] 2.1.1.37 [ KEGG ] 2.1.1.37 [ WIT ]
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo] negative regulation of transcription from RNA polymerase II promoter
GO	heterochromatin [Amigo] heterochromatin
GO	DNA binding [Amigo] DNA binding
GO	DNA (cytosine-5-)-methyltransferase activity [Amigo] DNA (cytosine-5-)-methyltransferase activity
GO	nucleus [Amigo] nucleus
GO	replication fork [Amigo] replication fork
GO	DNA methylation [Amigo] DNA methylation
GO	transcription [Amigo] transcription
GO	transcription factor binding [Amigo] transcription factor binding
GO	methyltransferase activity [Amigo] methyltransferase activity
GO	zinc ion binding [Amigo] zinc ion binding
GO	gene silencing [Amigo] gene silencing
GO	transcription repressor activity [Amigo] transcription repressor activity
GO	transferase activity [Amigo] transferase activity
GO	metal ion binding [Amigo] metal ion binding
KEGG	Methionine metabolism
PubGene	DNMT1
TreeFam	DNMT1
CTD	1786 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	DNMT1 Related clones (RZPD - Berlin)
	PubMed
PubMed	114 Pubmed reference(s) in LocusLink

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Kanai Y, Hirohashi S.

Carcinogenesis 2007; 28: 2434-2442 (Review).

PMID 17893234

Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion.

Sawada M, Kanai Y, Arai E, Ushijima S, Ojima H, Hirohashi S.

Cancer Lett 2007; 251:211-219.

PMID 17196739

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice.

Howard G, Eiges R, Gaudet F, Jaenisch R, Eden A.

Oncogene 2008; 27: 404-408.

PMID 17621273

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Written 03-2008 Eri 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jul 14 17:43:44 2008

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Other names	AIM
	DNMT
	DNA
	MCMT
	FLJ16293
	CXXC9
Hugo	DNMT1
Location	19p13.2

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.

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.
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.

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.

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.

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Written	03-2008	Eri Arai, Yae Kanai
		Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.