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

Alias (NCBI)	DNMT3A2
	M.HsaIIIA
HGNC (Hugo)	DNMT3A
HGNC Previous name	DNA (cytosine-5-)-methyltransferase 3 alpha
LocusID (NCBI)	1788
Atlas_Id	40349
Location	2p23.3  [Link to chromosome band 2p23]
Location_base_pair	Starts at 25281452 and ends at 25342590 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping DNMT3A.png]
Local_order	The human DNMT3A is telomeric to DTNB (dystrobrevin, beta) and centromeric to (proopiomelanocortin).
	Genomic localization of human DNMT3A gene. POMC, proopiomelanocortin; DTNB, dystrobrevin, beta.

	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).

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