DNMT3A (DNA (cytosine-5-)-methyltransferase 3 alpha)

2013-03-01   Yuan-Yeh Kuo , Li-Yu Li , Hwei-Fang Tien 

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan (YYK, LYL); Department of Internal Medicine, National Taiwan University Hospital, No.7, Chung-Shan S. Road, Taipei, Taiwan (HFT)


Atlas Image
Genomic localization of human DNMT3A gene. POMC, proopiomelanocortin; DTNB, dystrobrevin, beta.



The DNMT3A gene structure is composed of 23 exons (Xie et al., 1999). A short isoform, named DNMT3A2, is produced from a downstream intronic promoter (Chen et al., 2002).


Transcription of DNMT3A is initiated from the downstream intronic promoter and leads to expression of DNMT3A2, an isoform lacking the N-terminal region, in embryonic stem cells (ESCs). Expression of this shorter isoform gradually decreases upon ESC differentiation and switches to the full length DNMT3A which remains expressed at low level in most somatic tissues (Chedin, 2011; Chen et al., 2002).


Atlas Image
Structure of DNA methyltransferases. NLS, nuclear localization signal; CXXC, a cysteine rich region; BAH, a bromo-adjacent homology domain; PWWP, a proline-tryptophan-tryptophan-proline domain; ADD, an ATRX-DNMT3-DNMT3L-type zinc finger domain; Mtase, a methyltransferase domain.


AA: 912. EC number: Estimated molecular weight: 101858 Dt.
AA: 689. Estimated molecular weight: 77817 Dt.
DNMT3A contains 3 main structure domains: a proline-tryptophan-tryptophan-proline (PWWP) domain, an ATRX, DNMT3, and DNMT3L-type zinc finger (ADD) domain, and the methyltransferase (Mtase) domain. The PWWP domain is responsible for targeting the enzyme to nucleic acid (Chen et al., 2004). In addition, the PWWP domain is also essential for targeting this enzyme to pericentric heterochromatin (Chen et al., 2004; Ge et al., 2004). The ADD domain mediates protein-protein interactions with transcription factors Myc, RP58, the heterochromatin protein HP1, histone deacetylases, and the histone methyltransferase Suv39h1 (Chen and Li, 2006). The Mtase domain contains six highly conserved cytosine C5-DNA methyltransferase motifs (Jurkowska et al., 2011).


In mouse, Dnmt3a was detected in all tissues except for small intestines, whereas Dnmt3a2 expression was more restricted in testis, spleen and thymus (Chen et al., 2002). In addition to normal tissues, overexpression of DNMT3A has been reported in various human cancers, such as prostate, pancreatic, gastric, liver cancers (Gravina et al., 2013; Oh et al., 2007; Yang et al., 2011; Zhang et al., 2012). Additionally, DNMT3A were detected substantially overexpressed in certain types of leukemia (Mizuno et al., 2001).


Dnmt3a localizes in the nuclei and is concentrated in nuclear foci. In contrast, Dnmt3a2 showed a diffused pattern excluding nucleoli and heterochromatin. In general, Dnmt3a is thought to associate with heterochmatin, whereas Dnmt3a2 associates mainly with euchromatin (Chen et al., 2002).


Similarly to Dnmt1, the Dnmt3a enzyme also uses S-adenosyl methionine (SAM) as the methyl group donor being transferred to the carbon 5 position of the cytosine ring in CpG dinucleotide in DNA. It is essential for the establishment of DNA methylation patterns during development (Jurkowska et al., 2011).In addition to the enzymatic function, Dnmt3a was also shown to suppress transcription, independent of its catalytic activity, that was mediated through the interaction with the histone deacetylase and other co-repressors, such as Mbd3 and Brg1 (Datta et al., 2005; Fuks et al., 2001). Sumoylation of DNMT3A has been reported in the N-terminal domain of the enzyme, which disrupts its interaction with histone deacetylases (HDACs) and thereby impairs the repressive capability of this protein (Ling et al., 2004).


Dnmt3 family proteins share some structural similarity with Dnmt1 at c-terminal Mtase domain. In addition, the DNMT3A and DNMT3B proteins also contain a conserved cystein-rich ATRX, DNMT3, and DNMT3L-type zinc finger (ADD) domain and the proline-tryptophan-tryptophan-proline (PWWP) domain. The N-terminal domains of Dnmt3a and Dnmt3b do not share any sequence homology (Chedin, 2011).



Recurrent DNMT3A gene mutations were recently reported in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), T-cell lymphoma, and T-cell acute lymphoblastic leukemia (ALL) (Couronne et al., 2012; Grossmann et al., 2013; Hou et al., 2012; Ley et al., 2010; Stegelmann et al., 2011; Walter et al., 2011). The most frequently mutated site is the Arg 882 (R882) residue located in the catalytic domain. These R882 mutants were reported to reduce DNA methylation activity of DNMT3A (Yan et al., 2011).

Implicated in

Entity name
DNMT3A mutations frequently detected in 7-29% of AML patients. This mutation was associated with normal karyotype, older age, French-American-British (FAB) M4/M5 subtypes, and poor prognosis. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for over-all survival and relapse-free survival (Hou et al., 2012; Ley et al., 2010; Thol et al., 2011a; Yan et al., 2011). This mutation was also reported in 35.1% of secondary AML and 16.4% of therapy-related AML in a study of a cohort of 98 patients and found that this mutation was associated with normal karyotype and IDH1/IDH2 mutations, but that it does not affect survival (Shih et al., 2013). Recent reports further demonstrated that the frequency of DNMT3A mutations is rare in childhood AML and MDS, suggesting that the frequency of DNMT3A gene mutation depends on age (Ho et al., 2011; Thol et al., 2011b). In addition, it was also reported that AML patients whose leukemic blasts have low DNMT3A activity, either due to loss-of-functions or low gene expression, may benefit from treatment with hypomethylating agents (Metzeler et al., 2012).
Entity name
Myelodysplastic syndrome (MDS)
Mutations of the DNMT3A gene were detected in 6% of MDS patients and amino acid R882 was the most common mutation site. Patients with DNMT3A mutations had worse overall survival compared with patients without these mutations and more rapid progression to AML (Walter et al., 2011).
Entity name
Myeloproliferative neoplasms (MPN)
In a study of a cohort of 155 patients with MPN, an overall frequency of 10% mutations were most frequently detected in secondary AML (sAML: 17%) and myelofibrosis (MF: 15%), followed by polycythemia vera (PV: 7%) and essential thrombocythemia (ET: 3%). These alterations occurred concurrently with JAK2, IDH1/2 and ASXL1 mutations. In addition, these mutations are associated with more advanced stages of MPNs and with an overall poor prognosis (Stegelmann et al., 2011).
Entity name
T-cell lymphoma
DNMT3A mutations were reported in eleven of 98 patients with T-cell lymphoma and were associated with TET2 mutations (Couronne et al., 2012).
DNMT3A mutations were detected in 16 of 90 patients (17.8%) with T-ALL. These alterations were associated with normal karyotype, lower hemoglobin levels and mutually exclusive in cases with CDKN2A/CDKN2B deletions. Further, these mutations had a strong association with shorter overall survival (Grossmann et al., 2013).
Entity name
Lung cancer
Deletion of Dnmt3a significantly promotes tumor growth and progression in lung cancer mouse model, suggesting that this gene may act like a tumor-suppressor gene and may be a crucial factor of lung cancer malignancy (Gao et al., 2011).


Pubmed IDLast YearTitleAuthors
165708452006DNA methyltransferases: facts, clues, mysteries.Brenner C et al
215073542011The DNMT3 family of mammalian de novo DNA methyltransferases.Chédin F et al
165708482006Establishment and maintenance of DNA methylation patterns in mammals.Chen T et al
154568782004The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin.Chen T et al
121381112002A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation.Chen T et al
222168612012TET2 and DNMT3A mutations in human T-cell lymphoma.Couronné L et al
163222362005Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells.Datta J et al
200603652010DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.Figueroa ME et al
113509432001Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription.Fuks F et al
220115812011Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression.Gao Q et al
149989982004Chromatin targeting of de novo DNA methyltransferases by the PWWP domain.Ge YZ et al
232543862013Increased levels of DNA methyltransferases are associated with the tumorigenic capacity of prostate cancer cells.Gravina GL et al
233413442013The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL.Grossmann V et al
119348642002Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice.Hata K et al
155261632004Biochemistry and biology of mammalian DNA methyltransferases.Hermann A et al
215040502011Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group.Ho PA et al
220770612012DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications.Hou HA et al
212437102011Structure and function of mammalian DNA methyltransferases.Jurkowska RZ et al
210673772010DNMT3A mutations in acute myeloid leukemia.Ley TJ et al
147520482004Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription.Ling Y et al
211304082010Epigenetics in AML.Melnick AM et al
221242132012DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia.Metzeler KH et al
112223582001Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia.Mizuno S et al
175493902007DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation.Oh BK et al
172599672007Transcription factors in myeloid development: balancing differentiation with transformation.Rosenbauer F et al
233493052013Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia.Shih AH et al
215373342011DNMT3A mutations in myeloproliferative neoplasms.Stegelmann F et al
151054262004DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction.Suetake I et al
174202642007De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells.Tadokoro Y et al
216704482011Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.Thol F et al
216854662011DNMT3A mutations are rare in childhood acute myeloid leukemia.Thol F et al
197966242009DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells.Trowbridge JJ et al
214158522011Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.Walter MJ et al
104339691999Cloning, expression and chromosome locations of the human DNMT3 gene family.Xie S et al
213996342011Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.Yan XJ et al
218874662011Clinical significance of the expression of DNA methyltransferase proteins in gastric cancer.Yang J et al
223014002012Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma.Zhang JJ et al

Other Information

Locus ID:

NCBI: 1788
MIM: 602769
HGNC: 2978
Ensembl: ENSG00000119772


dbSNP: 1788
ClinVar: 1788
TCGA: ENSG00000119772


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
DNA methylationREACTOMER-HSA-5334118
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
RMTs methylate histone argininesREACTOMER-HSA-3214858

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166123431heart valve replacementDiseaseClinicalAnnotationassociatedPD27740732


Pubmed IDYearTitleCitations
178903172007MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B.617
210673772010DNMT3A mutations in acute myeloid leukemia.596
210673772010DNMT3A mutations in acute myeloid leukemia.596
202288042010Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.364
221386932011Dnmt3a is essential for hematopoietic stem cell differentiation.337
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
213996342011Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.275
192344652009PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.185
269697352016Repurposing the CRISPR-Cas9 system for targeted DNA methylation.178
214158522011Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.169


Yuan-Yeh Kuo ; Li-Yu Li ; Hwei-Fang Tien

DNMT3A (DNA (cytosine-5-)-methyltransferase 3 alpha)

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/gene/40349/dnmt3a-(dna-(cytosine-5-)-methyltransferase-3-alpha)