DNA (cytosine-5)-methyltransferase 3A

Function

Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1 (By similarity). Plays a role in paternal and maternal imprinting (By similarity). Required for methylation of most imprinted loci in germ cells (By similarity). Acts as a transcriptional corepressor for ZBTB18 (By similarity). Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites (By similarity). Can actively repress transcription through the recruitment of HDAC activity (By similarity). Also has weak auto-methylation activity on Cys-710 in absence of DNA (By similarity).

Classification

Family (Pfam)

PF17980 ADD_DNMT3, PF00145 DNA_methylase, PF22855 DNM3A_N, PF21255 DNMT3_ADD_GATA1-like, PF00855 PWWP

InterPro

ADD, ADD_DNMT3A, C5-Methyltransferase, C5_DNA_meth_AS, C5_MeTfrase, DNM3A_N, DNMT3_ADD_GATA1-like, DNMT3_ADD_PHD, PWWP_dom, SAM-dependent_MTases_sf

Functional cluster

Mixed Regulatory & Membrane Proteins

Experimental structures · PDB · 31

• 2QRV X-ray 2.89A
• 3A1A X-ray 2.30A
• 3A1B X-ray 2.29A
• 3LLR X-ray 2.30A
• 3SVM X-ray 2.31A
• 4QBQ X-ray 2.41A
• 4QBR X-ray 1.90A
• 4QBS X-ray 1.80A
• 4U7P X-ray 3.82A
• 4U7T X-ray 2.90A
• 5YX2 X-ray 2.65A
• 6BRR X-ray 2.97A
• … and 19 more

A predicted model is available from AlphaFold.

Gene Ontology · 37

• GO:0000775 chromosome, centromeric region
• GO:0005737 cytoplasm
• GO:0000791 euchromatin
• GO:0000792 heterochromatin
• GO:0016363 nuclear matrix
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0001741 XY body
• GO:0003682 chromatin binding
• GO:0003886 DNA (cytosine-5-)-methyltransferase activity
• GO:0003677 DNA binding
• GO:0106222 lncRNA binding
• GO:0106363 protein-cysteine methyltransferase activity
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:0003714 transcription corepressor activity
• GO:0045322 unmethylated CpG binding
• GO:0008270 zinc ion binding
• GO:0071361 cellular response to ethanol
• GO:0071456 cellular response to hypoxia
• GO:0006346 DNA methylation-dependent constitutive heterochromatin formation
• GO:0097284 hepatocyte apoptotic process
• GO:0032259 methylation
• GO:0045892 negative regulation of DNA-templated transcription
• GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0030182 neuron differentiation
• GO:1900039 positive regulation of cellular response to hypoxia
• GO:0031048 regulatory ncRNA-mediated heterochromatin formation
• GO:0042220 response to cocaine
• GO:0032355 response to estradiol
• GO:0010212 response to ionizing radiation
• GO:0010288 response to lead ion
• GO:0009636 response to toxic substance
• GO:0033189 response to vitamin A
• GO:0009410 response to xenobiotic stimulus
• GO:0141196 transposable element silencing by piRNA-mediated DNA methylation

Disease associations

• acute myeloid leukemia MONDO:0018874
• Tatton-Brown-Rahman overgrowth syndrome MONDO:0014382
• Heyn-Sproul-Jackson syndrome MONDO:0032882

Drugs targeting this protein · 2

• DECITABINE inhibitor
• AZACITIDINE inhibitor

Related proteins · sequence + function similarity

• DNA (cytosine-5)-methyltransferase 3A 1.00
• DNA (cytosine-5)-methyltransferase 3A 1.00
• DNA (cytosine-5)-methyltransferase 3A 0.99
• [F-actin]-monooxygenase MICAL3 0.81
• [F-actin]-monooxygenase MICAL3 0.81
• [F-actin]-monooxygenase MICAL3 0.80
• Protein-methionine sulfoxide oxidase mical3a 0.76
• Metastasis-associated protein MTA1 0.73
• Metastasis-associated protein MTA1 0.72
• Metastasis-associated protein MTA1 0.72
• Biorientation of chromosomes in cell division protein 1 0.72
• Biorientation of chromosomes in cell division protein 1 0.71

Co-cited proteins · studied together in the literature

• DNA (cytosine-5)-methyltransferase 3B 7 shared papers
• DNA (cytosine-5)-methyltransferase 3A 4 shared papers
• DNA (cytosine-5)-methyltransferase 3-like 1 shared papers
• M-phase phosphoprotein 8 2 shared papers
• DNA (cytosine-5)-methyltransferase 1 5 shared papers
• Histone-lysine N-methyltransferase SETD2 1 shared papers
• Lysine-specific demethylase 6A 1 shared papers
• Histone-lysine N-methyltransferase SETDB1 3 shared papers
• Histone-lysine N-methyltransferase EZH2 4 shared papers
• PWWP domain-containing DNA repair factor 3A 1 shared papers
• Histone-lysine N-methyltransferase EHMT1 1 shared papers
• Zinc finger protein 263 1 shared papers

Literature · 30 cited papers

• The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. Oncogene · 2020
• Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat. Genet. · 2019
• The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. Am. J. Med. Genet. A · 2017
• Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. J. Med. Genet. · 2017
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am. J. Med. Genet. A · 2017
• Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin. Genet. · 2017
• SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J. Med. Genet. · 2016
• Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat. Commun. · 2011
• Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood · 2011
• … and 18 more in the literature graph