DNMT3B (DNA (cytosine-5-)-methyltransferase 3 beta)

2012-07-01   Riadh Ben Gacem , Olfa Ben Abdelkrim , Sonia Ziadi , Mounir Trimeche 

Department of Pathology, Farhat-Hached Hospital, Sousse, Tunisia




Atlas Image
Figure 1. DNMT3B gene is located on the long arm of chromosome 20 at position 11.2 from the base pair 31350190 to base pair 31397161. It is composed of 23 exons and 22 introns.


DNMT3B gene is located on the long arm of chromosome 20 at position 11.2 and is composed of 23 exons and 22 introns. This gene encodes for a protein of 853 aa. DNMT3B gene is abundantly expressed in embryonic stem cells, but its expression is decreased upon their differentiation and remains low in adult somatic tissues.


Primary transcript of DNMT3B gene can be spliced five different mRNA isoforms that are DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4 and DNMT3B5.



DNMT3B protein is structured with N-terminal regulatory and C-terminal catalytic domains that are linked by repeated GK dipeptides (Glycine-Lysine-repeats). The N-terminal domain possesses nuclear localization signal sequence (NLS) responsible for nucleus DNMT3B localization. The N-terminal domain plays a regulatory role, and contains a proliferating cell nuclear antigen-binding domain. This N-domain also contains a cysteine rich zinc finger DNA binding motif (ATRX), a polybromo homology domain (PHD) targeting DNMT3B to the replication foci and a PWWP tetrapeptide chromatin-binding domain (Margot et al., 2000). The two halves are packed against each other to form a single structural module that exhibits a prominent positive electrostatic potential. The PWWP domain of DNMT3B alone binds DNA in vitro, probably through its basic surface, and DNMT3B binds DNA stronger than a mutant without the domain. In addition, the PWWP domain seems to target the de novo methyltransferases to chromatin. The C-terminal domain contains six conservative motifs I, IV, VI, VIII, IX and X. Motif I and X are involved in the formation of the S-adenosylomethionine binding site. Motif IV binds the substrate cytosine at the active site. Motif VI contains the glutamyl residue serving as a proton donor. Motif IX maintains the structure of the target recognition domain (TRD). Motif VIIIs function is unclear (Xie et al., 1999).
The intracellular distribution of DNMT3B enzyme is rather dynamic throughout the cell cycle, indeed this enzyme is diffusely distributed throughout the nucleoplasm during most of G1, associates with subnuclear sites of DNA replication during S-phase (Leonhardt et al.,1992), and binds to chromatin, with preference to pericentric heterochromatin, during G2 and M-phases (Easwaran et al., 2005).


853 amino acids; 95751 Da.
Atlas Image
Figure 2. A: The general structure of DNMT3B protein. The N-terminal domain contains a proliferating cell nuclear antigen-binding domain, a nuclear localization signal, a tetrapeptide PWWP, essential for DNMT binding to chromatin, an ATRX cysteine-rich zinc finger DNA-binding motif and a polybromo homology domain (PHD) targeting DNMT3B to the replication foci. The C-terminal catalytic domain of DNMT3B is characterized by the presence of 6 conserved amino acid motifs, namely I, IV, VI, VIII, IX and X. Motifs I and X form S-adenosylomethionine binding site, motif IV binds cytosine at the active site, motif VI possesses glutamyl residue donating protons, and motif IX maintains the structure of the target recognition domain (TRD) usually located between motifs VIII and IX, that make base-specific contacts in the major groove of DNA (Turek-Plewa and Jagodzinski, 2005). B: The results from alternative splicing of exons 10, 21 and/or 22, have reported several different transcripts of DNMT3B. These isoforms are: DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4 and DNMT3B5. DNMT3B1 and DNMT3B2, contain all the highly conserved motifs I, IV, VI, IX and X, are enzymatically active in DNA methyltransferase essays. DNMT3B3, which lacks parts of motif IX, appears to be inactive enzyme. DNMT3B4 and DNMT3B5, encode truncated proteins that lack motifs IX and X, are presumably inactive as well. The lack motifs in DNMT3B3, DNMT3B4 and DNMT3B5 are a consequence of lack 21-22, 21 or 22 exons, respectively (Xie et al., 1999; Okano et al., 1999).




DNMT3B is expressed at very low levels in most tissues except the testis, thyroid and bone marrow (Xie et al., 1999). DNMT3B level is profoundly increased in various tumor cell lines, indicating that it plays an important role in tumorigenesis (Robertson et al., 1999; Hermann et al., 2004). DNA methylation is a covalent chemical modification, resulting in the addition of a methyl (CH3) group at the carbon 5 position of the cytosine ring. DNMT3B uses S-adenosyl-L-methionine (AdoMet) as the source of the methyl group being transferred to the DNA bases. The methyl group of S-adenosylomethionine is bound to a sulphonium atom, which thermodynamically destabilizes the molecule and makes the relatively inert methylthiol of the methionine moiety very reactive towards nucleophilic attack by nitrogen, oxygen and sulphur atoms or activated C atoms (carbanions).
DNMT3B may also interact with DNMT1 and activate HDAC1, which deacetylates histones and represses gene transcription. This indicates that DNMT3B may be involved in chromatin remodeling associated with the modulation of gene transcription. DNMT3B can also effectively methylate C to m5C post-replicatively in unmethylated DNA. During or after replication, DNA regions may bind sequence-specific proteins which block the attachment of the methyl group to CpG dinucleotide and the formation of methylation patterns unique for each tissue. The existence of DNMT3B isoforms suggests that other factors can be involved in the binding of DNMT3B to a particular DNA region. Consequences of alternative splicing on DNMT3Bs ability to interact with DNMT3L. DNMT3L stimulates the catalytic activity of DNMT3A and DNMT3B methyltransferases (Suetake et al., 2004). DNMT3L binds to the carboxyl-terminal part of DNMT3B and increases the level of activity of this enzyme (Suetake et al., 2004).


DNMT3B exhibit a high degree of primary structure homology with DNMT3A. Structurally, DNMT3B and DNMT3A have a similar organization, with conserved domains: the long N-terminal region contains a PWWP domain and a cysteine-rich PHD zinc finger domain and the C-terminal catalytic domain. The same NLS and ATRX sequences were also founded in the DNMT3B and DNMT3A enzymes.



ICF syndrome (standing for Immunodeficiency, Centromere instability and Facial anomalies syndrome) is a rare autosomal recessive immune disorder caused by mutations of the gene DNMT3B. Therefore, the DNMT3B mutations, like A766P and R840Q, observed in patients are the likely underlying cause of their ICF phenotypes (Xie et al., 2006).
This hereditary syndrome is characterized by centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in their pericentromeric satellite regions (Hansen et al., 1999). At the molecular level, in patient DNA, sequences such as the pericentromeric classic satellite repeats of pericentromeric regions are hypomethylated, which attributes to reduced enzymatic activity of the mutant proteins (Jeanpierre et al., 1993; Gowher and Jeltsch, 2002).
Several polymorphisms were detected at the promoter region of DNMT3B gene and may influence its activity in DNA methylation and increase the susceptibility to several cancers. DNMT3B promoter polymorphisms influence on promoter hypermethylation of genes in other interacting pathways, such as cell cycle, apoptosis, or other DNA repair pathways and may increase level of DNA damage which contributes to an increased risk for cancers. For example, C>T (rs406193), -283T>C (rs121909506), -579G>T (rs2424909), -579G>T (rs2235758) and G39179T DNMT3B polymorphisms influence DNMT3B expression, thus contributing to the genetic susceptibility to different cancers (Lee et al., 2005; Fan et al., 2008; Montgomery et al., 2004; de Vogel et al., 2009; Daraei et al., 2011).
The common DNMT3B -149C>T (rs2424913) polymorphism was found to significantly increase DNTM3B promoter activity. This up-regulates the expression of the gene and may in turn lead to aberrant methylation of CpG islands in some tumor suppressor genes (Montgomery et al., 2004). It was associated with an increased risk for lung cancer (Shen et al., 2002), prostate cancer (Singal et al., 2005), and colorectal polyps, including colorectal adenomas (Jung et al., 2008), or with prognosis of head and neck cancer (Wang et al., 2004).

Implicated in

Entity name
Lung cancer
DNMT3B may play an oncogenic role during tumorigenesis, and its genetic variants have been consistently associated with risk of several cancers. Overexpression of DNMT3B may result in promoter hypermethylation of multiple tumor suppressor genes and ultimately lead to lung tumorigenesis and poor prognosis especially among smoking patients (Lin et al., 2007; Palakurthy et al., 2009).
Polymorphisms and haplotypes of the DNMT3B gene may influence DNMT3B activity on DNA methylation, thereby modulating the susceptibility to lung cancer. The -283T>C and -579G>T polymorphisms in the DNMT3B promoter, and their haplotypes were significantly associated with the risk of adenocarcinoma of the lung (Lee et al., 2005). These mutations up-regulate DNMT3B expression, resulting in a predisposition towards aberrant de novo methylation of CpG islands in tumor suppressor genes and DNA repair genes (Lee et al., 2005; Shen et al., 2002).
Entity name
Breast cancer
DNMT3B expression levels are significantly higher in breast cancers than in normal breast tissues, suggesting a role of this enzyme in breast tumorigenesis (Fig. 3) (Girault et al., 2003; Butcher and Rodenhiser, 2007; Ben Gacem et al., 2012). DNMT3B overexpression is correlated to the epigenetic inactivation of several tumor suppressor genes and to the aggressive phenotype in breast tumors (Roll et al., 2008; Ben Gacem et al., 2012). Some polymorphisms are associated to the development of breast tumors. DNMT3B C46359T polymorphism has been correlated to women with early-onset breast cancer, bilateral breast cancer and with a family history of the disease (Montgomery et al., 2004; Wang et al., 2004).
Atlas Image
Figure 3: DNMT3B overexpression in breast cancer cells as detected by immunocytochemistry (original magnification x400).
Entity name
Leukemia and lymphomas
DNMT3B is substantially overexpressed in leukemia cells than in normal bone marrow cells (Mizuno et al., 2001). DNMT3B overexpression was correlated to hypermethylation of several tumor related genes in diffuse large B-cell lymphomas and in B-cell chronic lymphocytic leukemia (Amara et al., 2010; Kn et al., 2004). In B-cell chronic lymphocytic leukemia, DNMT3B overexpression was identified as an independent prognostic factor for predicting shortened survival of patients (Amara et al., 2010).
Entity name
Hepatocellular carcinoma
DNA hypomethylation on pericentromeric satellite regions is one of the earliest events during hepatocarcinogenesis. Overexpression of DNMT3B4 isoform and elevation of the ratio of DNMT3B4 mRNA to DNMT3B3 mRNA were both significantly correlated with the degree of DNA hypomethylation on pericentromeric satellite regions in hepatocellular carcinoma (Saito et al., 2002). DNMT3B4 overexpression induces DNA demethylation on pericentromeric satellite regions even in precancerous stages and may play critical roles in the development of hepatocellular carcinoma through chromosomal instability and aberrant expression of cancer-related genes (Saito et al., 2002).
Entity name
Colorectal cancer
The levels of DNMTs mRNA/protein in colorectal carcinomas are significantly higher than in noncancerous colorectal tissues and the highest expression range was observed with DNMT3B (Eads et al., 1999; Linhart et al., 2007; Nosho et al., 2009; Huidobro et al., 2012). The CpG island methylator phenotype (CIMP) in colorectal cancer is characterized by a widespread CpG island methylation. DNMT3B contributes to CpG island methylation, which may eventually lead to the development of CIMP-high colorectal cancer (Nosho et al., 2009; Schmidt et al., 2007).
In hereditary nonpolyposis colorectal cancer, the DNMT3B gene contains a C-to-T single nucleotide polymorphism -149 bp from the transcriptional start site that may result in increased promoter activity of the gene (Shen et al., 2002). The DNA mismatch repair mutation carriers who also carried at least one T allele for the DNMT3B promoter region C-to-T polymorphism had a 2-fold higher risk for colorectal cancer by year than those who were homozygous for the wild-type DNMT3B allele (Jones et al., 2006).
Entity name
Facial anomalies syndrome (ICF)
Facial anomalies syndrome (ICF) is an autosomal recessive disease. DNMT3B gene is often the site of ICF mutations (Ehrlich et al., 2006). ICF syndrome presents with variable combined immunodeficiency, mild facial anomalies and extravagant cytogenetic abnormalities with largely affect the pericentric regions of chromosomes 1, 9 and 16. These pericentric regions contain a type of satellite DNA termed classical satellite, or satellites 2 and 3. It is normally heavily methylated, but is nearly completely unmethylated in DNA of ICF patients. In addition to classical satellite, demethylation of DNA in ICF patients is also seen at CpG islands on the inactivate X chromosome in females (Ehrlich et al., 2008).


Pubmed IDLast YearTitleAuthors
203980542010DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas.Amara K et al
225209502012Clinicopathologic significance of DNA methyltransferase 1, 3a, and 3b overexpression in Tunisian breast cancers.Ben Gacem R et al
170710742007Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours.Butcher DT et al
220913112011DNA-methyltransferase 3B 39179 G > T polymorphism and risk of sporadic colorectal cancer in a subset of Iranian population.Daraei A et al
103447331999CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression.Eads CA et al
157019672005Cell cycle markers for live cell analyses.Easwaran HP et al
167226022006Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF).Ehrlich M et al
184324062008ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation.Ehrlich M et al
186623742008Promoter polymorphisms of DNMT3B and the risk of colorectal cancer in Chinese: a case-control study.Fan H et al
145555142003Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas.Girault I et al
119192022002Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases.Gowher H et al
105887191999The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.Hansen RS et al
155261632004Biochemistry and biology of mammalian DNA methyltransferases.Hermann A et al
222448282012A DNA methylation signature associated with aberrant promoter DNA hypermethylation of DNMT3B in human colorectal cancer.Huidobro C et al
81025701993An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome.Jeanpierre M et al
167023652006DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset.Jones JS et al
182681162008DNA methyltransferase and alcohol dehydrogenase: gene-nutrient interactions in relation to risk of colorectal polyps.Jung AY et al
154674272004Expression analysis of the epigenetic methyltransferases and methyl-CpG binding protein families in the normal B-cell and B-cell chronic lymphocytic leukemia (CLL).Kn H et al
155282202005DNMT3B polymorphisms and risk of primary lung cancer.Lee SJ et al
14236341992A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei.Leonhardt H et al
171406952007Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer.Lin RK et al
180564242007Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing.Linhart HG et al
107152012000Structure and function of the mouse DNA methyltransferase gene: Dnmt1 shows a tripartite structure.Margot JB et al
112223582001Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia.Mizuno S et al
152175062004The DNMT3B C-->T promoter polymorphism and risk of breast cancer in a British population: a case-control study.Montgomery KG et al
105551411999DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.Okano M et al
198541322009Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression.Palakurthy RK et al
103254161999The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.Robertson KD et al
182215362008DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines.Roll JD et al
121107322002Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis.Saito Y et al
175389452007Progressive up-regulation of genes encoding DNA methyltransferases in the colorectal adenoma-carcinoma sequence.Schmidt WM et al
122087512002A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer.Shen H et al
160127462005Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk.Singal R et al
151054262004DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction.Suetake I et al
163412722005The role of mammalian DNA methyltransferases in the regulation of gene expression.Turek-Plewa J et al
153755492004A novel C/T polymorphism in the core promoter of human de novo cytosine DNA methyltransferase 3B6 is associated with prognosis in head and neck cancer.Wang L et al
104339691999Cloning, expression and chromosome locations of the human DNMT3 gene family.Xie S et al
165433612006Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L.Xie ZH et al
198436712009Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer.de Vogel S et al

Other Information

Locus ID:

NCBI: 1789
MIM: 602900
HGNC: 2979
Ensembl: ENSG00000088305


dbSNP: 1789
ClinVar: 1789
TCGA: ENSG00000088305


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
178903172007MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B.617
119327492002DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.393
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
183677142008miR-148 targets human DNMT3b protein coding region.217
209525352010Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes.190
258220892015Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells.127
179918952008DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B.121
145555142003Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas.100
180293872008DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.92
121452182002Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases.89


Riadh Ben Gacem ; Olfa Ben Abdelkrim ; Sonia Ziadi ; Mounir Trimeche

DNMT3B (DNA (cytosine-5-)-methyltransferase 3 beta)

Atlas Genet Cytogenet Oncol Haematol. 2012-07-01

Online version: http://atlasgeneticsoncology.org/gene/40350/dnmt3b-(dna-(cytosine-5-)-methyltransferase-3-beta)