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

Written2013-03Yuan-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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDNA (cytosine-5-)-methyltransferase 3 alpha
Other aliasDNMT3A2
M.HsaIIIA
HGNC (Hugo) DNMT3A
LocusID (NCBI) 1788
Atlas_Id 40349
Location 2p23.3  [Link to chromosome band 2p23]
Location_base_pair Starts at 25281452 and ends at 25341915 bp from pter ( according to hg19-Feb_2009)  [Mapping DNMT3A.png]
Local_order The human DNMT3A is telomeric to DTNB (dystrobrevin, beta) and centromeric to POMC (proopiomelanocortin).
 
  Genomic localization of human DNMT3A gene. POMC, proopiomelanocortin; DTNB, dystrobrevin, beta.
Fusion genes
(updated 2016)
DNMT3A (2p23.3) / ADCY3 (2p23.3)DNMT3A (2p23.3) / NUMA1 (11q13.4)DNMT3A (2p23.3) / TRPC6 (11q22.1)
Note DNA methylation occurs mainly in the cytosine residues at the C5 positions of CpG dinucleotides and is important in regulating gene expression, parental imprinting, and maintenance of the genome integrity in mammalian cells (Chen and Li, 2006). Aberrant DNA methylation has been reported to play a vital role in the pathogenesis of acute myeloid leukemia (AML) (Rosenbauer and Tenen, 2007). In addition, differences in global DNA methylation signatures have been reported to be associated with differences in treatment outcome for patients with AML (Figueroa et al., 2010a; Figueroa et al., 2010b; Melnick, 2010).
Genome-wide DNA methylation patterns are established and maintained by the coordination of DNMT1 and DNMT3 families of DNA methyltransferases. DNMT1 carries out most of the maintenance methylation following DNA replication, whereas DNMT3A and DNMT3B are responsible for de novo methylation during mammalian development (Brenner and Fuks, 2006; Hermann et al., 2004). Recent studies showed that Dnmt1 is required for hematopoietic stem cell proliferation and myeloid/lymphoid differentiation (Trowbridge et al., 2009). In contrast, conditional deletion of Dnmt3a and Dnmt3b in mouse hematopoietic stem cells impaired self- renewal but not lineage determination, indicating the role of de novo DNA methyltransferase for self-renewal in hematopoietic stem cells (Tadokoro et al., 2007). The third member of the DNMT3 family is DNMT3L which does not have enzymatic activity due to the lack of some critical catalytic motifs (Brenner and Fuks, 2006). It regulates the catalytic activity of DNMT3A and 3B (Hata et al., 2002; Suetake et al., 2004).

DNA/RNA

Description 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 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).

Protein

 
  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.
Description DNMT3A
AA: 912. EC number: 2.1.1.37. Estimated molecular weight: 101858 Dt.
DNMT3A2
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).
Expression 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).
Localisation 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).
Function 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).
Homology 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).

Mutations

Somatic 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

Note
  
Entity Acute myeloid leukemia (AML)
Note 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 Myelodysplastic syndrome (MDS)
Note 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 Myeloproliferative neoplasms (MPN)
Note 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 T-cell lymphoma
Note DNMT3A mutations were reported in eleven of 98 patients with T-cell lymphoma and were associated with TET2 mutations (Couronne et al., 2012).
  
  
Entity T-cell acute lymphoblastic leukemia (T-ALL)
Note 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 Lung cancer
Note 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).
  

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Citation

This paper should be referenced as such :
Kuo, YY ; Li, LY ; Tien, HF
DNMT3A (DNA (cytosine-5-)-methyltransferase 3 alpha)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(9):589-593.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/DNMT3AID40349ch2p23.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  Classification of myelodysplastic syndromes 2015
Chronic Myelomonocytic Leukemia (CMML)
Early T-cell precursor acute lymphoblastic leukemia


External links

Nomenclature
HGNC (Hugo)DNMT3A   2978
LRG (Locus Reference Genomic)LRG_459
Cards
AtlasDNMT3AID40349ch2p23
Entrez_Gene (NCBI)DNMT3A  1788  DNA methyltransferase 3 alpha
AliasesDNMT3A2; M.HsaIIIA; TBRS
GeneCards (Weizmann)DNMT3A
Ensembl hg19 (Hinxton)ENSG00000119772 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000119772 [Gene_View]  chr2:25281452-25341915 [Contig_View]  DNMT3A [Vega]
ICGC DataPortalENSG00000119772
TCGA cBioPortalDNMT3A
AceView (NCBI)DNMT3A
Genatlas (Paris)DNMT3A
WikiGenes1788
SOURCE (Princeton)DNMT3A
Genetics Home Reference (NIH)DNMT3A
Genomic and cartography
GoldenPath hg38 (UCSC)DNMT3A  -     chr2:25281452-25341915 -  2p23.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DNMT3A  -     2p23.3   [Description]    (hg19-Feb_2009)
EnsemblDNMT3A - 2p23.3 [CytoView hg19]  DNMT3A - 2p23.3 [CytoView hg38]
Mapping of homologs : NCBIDNMT3A [Mapview hg19]  DNMT3A [Mapview hg38]
OMIM602769   615879   
Gene and transcription
Genbank (Entrez)AB208833 AF067972 AF331856 AF480163 AI376254
RefSeq transcript (Entrez)NM_001320892 NM_001320893 NM_022552 NM_153759 NM_175629 NM_175630
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)DNMT3A
Cluster EST : UnigeneHs.515840 [ NCBI ]
CGAP (NCI)Hs.515840
Alternative Splicing GalleryENSG00000119772
Gene ExpressionDNMT3A [ NCBI-GEO ]   DNMT3A [ EBI - ARRAY_EXPRESS ]   DNMT3A [ SEEK ]   DNMT3A [ MEM ]
Gene Expression Viewer (FireBrowse)DNMT3A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1788
GTEX Portal (Tissue expression)DNMT3A
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y6K1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y6K1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y6K1
Splice isoforms : SwissVarQ9Y6K1
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 ]   
PhosPhoSitePlusQ9Y6K1
Domaine pattern : Prosite (Expaxy)ADD (PS51533)    C5_MTASE_1 (PS00094)    PWWP (PS50812)    SAM_MT_C5 (PS51679)   
Domains : Interpro (EBI)ADD    C5_DNA_meth_AS    C5_MeTfrase    DNMT3A    PWWP_dom    SAM-dependent_MTases   
Domain families : Pfam (Sanger)DNA_methylase (PF00145)    PWWP (PF00855)   
Domain families : Pfam (NCBI)pfam00145    pfam00855   
Domain families : Smart (EMBL)PWWP (SM00293)  
Conserved Domain (NCBI)DNMT3A
DMDM Disease mutations1788
Blocks (Seattle)DNMT3A
PDB (SRS)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
PDB (PDBSum)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
PDB (IMB)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
PDB (RSDB)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
Structural Biology KnowledgeBase2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
SCOP (Structural Classification of Proteins)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
CATH (Classification of proteins structures)2QRV    3A1A    3A1B    3LLR    3SVM    4QBQ    4QBR    4QBS    4U7P    4U7T   
SuperfamilyQ9Y6K1
Human Protein AtlasENSG00000119772
Peptide AtlasQ9Y6K1
HPRD04141
IPIIPI00329216   IPI00893229   IPI00328540   IPI00220006   IPI00893896   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y6K1
IntAct (EBI)Q9Y6K1
FunCoupENSG00000119772
BioGRIDDNMT3A
STRING (EMBL)DNMT3A
ZODIACDNMT3A
Ontologies - Pathways
QuickGOQ9Y6K1
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  mitotic cell cycle  chromosome, centromeric region  euchromatin  XY body  DNA binding  chromatin binding  DNA (cytosine-5-)-methyltransferase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nuclear heterochromatin  cytoplasm  DNA methylation  methylation-dependent chromatin silencing  regulation of gene expression by genetic imprinting  spermatogenesis  aging  DNA-methyltransferase activity  response to toxic substance  response to ionizing radiation  response to lead ion  positive regulation of cell death  nuclear matrix  neuron differentiation  response to estradiol  response to vitamin A  response to cocaine  response to drug  identical protein binding  DNA methylation involved in embryo development  DNA methylation involved in gamete generation  negative regulation of gene expression, epigenetic  metal ion binding  cellular response to amino acid stimulus  cellular response to ethanol  cellular response to hypoxia  C-5 methylation of cytosine  hepatocyte apoptotic process  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  mitotic cell cycle  chromosome, centromeric region  euchromatin  XY body  DNA binding  chromatin binding  DNA (cytosine-5-)-methyltransferase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nuclear heterochromatin  cytoplasm  DNA methylation  methylation-dependent chromatin silencing  regulation of gene expression by genetic imprinting  spermatogenesis  aging  DNA-methyltransferase activity  response to toxic substance  response to ionizing radiation  response to lead ion  positive regulation of cell death  nuclear matrix  neuron differentiation  response to estradiol  response to vitamin A  response to cocaine  response to drug  identical protein binding  DNA methylation involved in embryo development  DNA methylation involved in gamete generation  negative regulation of gene expression, epigenetic  metal ion binding  cellular response to amino acid stimulus  cellular response to ethanol  cellular response to hypoxia  C-5 methylation of cytosine  hepatocyte apoptotic process  
Pathways : KEGGCysteine and methionine metabolism    MicroRNAs in cancer   
REACTOMEQ9Y6K1 [protein]
REACTOME PathwaysR-HSA-5334118 [pathway]   
NDEx NetworkDNMT3A
Atlas of Cancer Signalling NetworkDNMT3A
Wikipedia pathwaysDNMT3A
Orthology - Evolution
OrthoDB1788
GeneTree (enSembl)ENSG00000119772
Phylogenetic Trees/Animal Genes : TreeFamDNMT3A
HOVERGENQ9Y6K1
HOGENOMQ9Y6K1
Homologs : HomoloGeneDNMT3A
Homology/Alignments : Family Browser (UCSC)DNMT3A
Gene fusions - Rearrangements
Fusion : MitelmanDNMT3A/TRPC6 [2p23.3/11q22.1]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDNMT3A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DNMT3A
dbVarDNMT3A
ClinVarDNMT3A
1000_GenomesDNMT3A 
Exome Variant ServerDNMT3A
ExAC (Exome Aggregation Consortium)DNMT3A (select the gene name)
Genetic variants : HAPMAP1788
Genomic Variants (DGV)DNMT3A [DGVbeta]
DECIPHERDNMT3A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDNMT3A 
Mutations
ICGC Data PortalDNMT3A 
TCGA Data PortalDNMT3A 
Broad Tumor PortalDNMT3A
OASIS PortalDNMT3A [ Somatic mutations - Copy number]
Cancer Gene: CensusDNMT3A 
Somatic Mutations in Cancer : COSMICDNMT3A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDNMT3A
intOGen PortalDNMT3A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch DNMT3A
DgiDB (Drug Gene Interaction Database)DNMT3A
DoCM (Curated mutations)DNMT3A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DNMT3A (select a term)
intoGenDNMT3A
NCG5 (London)DNMT3A
Cancer3DDNMT3A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602769    615879   
Orphanet22920   
MedgenDNMT3A
Genetic Testing Registry DNMT3A
NextProtQ9Y6K1 [Medical]
TSGene1788
GENETestsDNMT3A
Target ValidationDNMT3A
Huge Navigator DNMT3A [HugePedia]
snp3D : Map Gene to Disease1788
BioCentury BCIQDNMT3A
ClinGenDNMT3A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1788
Chemical/Pharm GKB GenePA27445
Clinical trialDNMT3A
Miscellaneous
canSAR (ICR)DNMT3A (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=DNMT3A
Probes
Litterature
PubMed288 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDNMT3A
EVEXDNMT3A
GoPubMedDNMT3A
iHOPDNMT3A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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