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CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]
DNMT3A is one of several epigenetic modifiers identified as recurrently mutated in acute myeloid leukemia (AML). DNMT3A mutations are associated with cytogenetically normal AML. In vitro experiments indicate that the R882H mutation acts in a dominant negative manner to disrupt the de novo methyltransferase activity of wildtype homotetramers. AML patient bone marrow harboring R882 mutations were similarly demonstrated to be hypomethylated compared to patients with wildtype DNMT3A. These studies also indicated that non-R882 DNMT3A mutations may act in a functionally distinct manner from R882 mutations. Alternative mechanisms indicate independent prognostic outcomes and treatment protocols may need to be considered for these two classes of DNMT3A mutations.
DNMT3A (DNA Methyltransferase 3 Alpha) is a Protein Coding gene. Diseases associated with DNMT3A include Tatton-Brown-Rahman Syndrome and Heyn-Sproul-Jackson Syndrome. Among its related pathways are One carbon pool by folate and Validated targets of C-MYC transcriptional repression. Gene Ontology (GO) annotations related to this gene include identical protein binding and methyltransferase activity. An important paralog of this gene is DNMT3B.
Protein arginine methyltransferases are enyzmes that catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to the arginine residues on histones and other proteins. The dysregulation of this methylation is critical in the development of certain cancers.
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000978 | RNA polymerase II proximal promoter sequence-specific DNA binding | IDA | 19786833 |
GO:0003677 | DNA binding | IEA,IDA | 12138111 |
GO:0003682 | chromatin binding | IEA | -- |
GO:0003714 | transcription corepressor activity | TAS | 19786833 |
GO:0003886 | DNA (cytosine-5-)-methyltransferase activity | IEA,IDA | 12138111 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000775 | chromosome, centromeric region | IEA | -- |
GO:0000791 | euchromatin | IDA | 12138111 |
GO:0000792 | heterochromatin | IEA | -- |
GO:0001741 | XY body | IEA | -- |
GO:0005634 | nucleus | IEA,IDA | 12138111 |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 |
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2 | One carbon pool by folate |
Methionine metabolism
.34
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3 | Chromatin organization | ||
4 | Chromatin Regulation / Acetylation | ||
5 | Sulfur amino acid metabolism |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000122 | negative regulation of transcription by RNA polymerase II | IMP | 19786833 |
GO:0000278 | mitotic cell cycle | IEA | -- |
GO:0006306 | DNA methylation | IDA,IMP | 30478443 |
GO:0006325 | chromatin organization | IEA | -- |
GO:0006346 | methylation-dependent chromatin silencing | IEA | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
Procaine | Approved, Investigational, Vet_approved | Pharma | Channel blocker, Target, inhibitor | 52 | ||
Warfarin | Approved | Pharma | 609 | |||
Thioguanine | Approved | Pharma | Purine antimetabolite | 89 | ||
Decitabine | Approved, Investigational | Pharma | DNA methyltransferase inhibitor | 388 | ||
Zebularine | Experimental | Pharma | DNA methylation inhibitor, DNA methyltransferase and cytidine deaminase inhibitor | 0 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs | |
---|---|---|---|---|---|---|
5-methylcytosine |
|
554-01-8 | ||||
s-adenosylmethionine |
|
485-80-3 |
Compound | Action | Cas Number |
---|---|---|
5-Azacytidine | DNA methyltransferase inhibitor | 320-67-2 |
Decitabine | DNA methyltransferase inhibitor | 2353-33-5 |
Lomeguatrib | MGMT inhibitor | 192441-08-0 |
RG 108 | Non-nucleoside DNA methyltransferase inhibitor | 48208-26-0 |
Zebularine | DNA methyltransferase and cytidine deaminase inhibitor | 3690-10-6 |
Compound | Action | Cas Number |
---|---|---|
5-Azacytidine | DNA methyltransferase inhibitor. | 320-67-2 |
Decitabine (NSC127716, 5AZA-CdR) | Deoxycytidine analog and cellular diifferentiation inducer | 2353-33-5 |
Lomeguatrib | MGMT inhibitor | 192441-08-0 |
RG 108 | DNA methyltransferase inhibitor | 48208-26-0 |
SGI-1027 | DNMT inhibitor | 1020149-73-8 |
Thioguanine | Purine antimetabolite | 154-42-7 |
Zebularine | DNA methylation inhibitor | 3690-10-6 |
ExUns: | 1a | · | 1b | ^ | 2 | ^ | 3a | · | 3b | · | 3c | ^ | 4 | ^ | 5 | ^ | 6 | ^ | 7a | · | 7b | ^ | 8 | ^ | 9a | · | 9b | · | 9c | ^ | 10 | ^ | 11a | · | 11b | ^ | 12a | · | 12b | ^ | 13a | · | 13b | · | 13c | ^ | 14 | ^ | 15 | ^ | 16 | ^ |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||||
SP2: | ||||||||||||||||||||||||||||||||||||||||||||||||||||
SP3: | ||||||||||||||||||||||||||||||||||||||||||||||||||||
SP4: | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||
SP5: | - | |||||||||||||||||||||||||||||||||||||||||||||||||||
SP6: | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||
SP7: | - | - | ||||||||||||||||||||||||||||||||||||||||||||||||||
SP8: | - | |||||||||||||||||||||||||||||||||||||||||||||||||||
SP9: | ||||||||||||||||||||||||||||||||||||||||||||||||||||
SP10: | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||||
SP11: |
ExUns: | 17 | ^ | 18 | ^ | 19a | · | 19b | ^ | 20a | · | 20b | · | 20c | ^ | 21 | ^ | 22 | ^ | 23a | · | 23b | ^ | 24a | · | 24b | ^ | 25 | ^ | 26 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | |||||||||||||||||||||||||||
SP2: | - | ||||||||||||||||||||||||||||
SP3: | |||||||||||||||||||||||||||||
SP4: | |||||||||||||||||||||||||||||
SP5: | |||||||||||||||||||||||||||||
SP6: | |||||||||||||||||||||||||||||
SP7: | |||||||||||||||||||||||||||||
SP8: | |||||||||||||||||||||||||||||
SP9: | |||||||||||||||||||||||||||||
SP10: | |||||||||||||||||||||||||||||
SP11: |
This gene was present in the common ancestor of chordates.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | DNMT3A 30 31 |
|
OneToOne | |
Platypus (Ornithorhynchus anatinus) |
Mammalia | -- 31 |
|
OneToMany | |
-- 31 |
|
OneToMany | |||
Dog (Canis familiaris) |
Mammalia | DNMT3A 31 |
|
OneToOne | |
LOC482996 30 |
|
||||
Oppossum (Monodelphis domestica) |
Mammalia | -- 31 |
|
OneToMany | |
-- 31 |
|
OneToMany | |||
Cow (Bos Taurus) |
Mammalia | DNMT3A 30 31 |
|
OneToOne | |
Mouse (Mus musculus) |
Mammalia | Dnmt3a 30 17 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Dnmt3a 30 |
|
||
Chicken (Gallus gallus) |
Aves | DNMT3A 30 31 |
|
OneToOne | |
Lizard (Anolis carolinensis) |
Reptilia | DNMT3A 31 |
|
OneToOne | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | LOC100496503 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | dnmt3ab 30 31 |
|
OneToMany | |
dnmt3aa 31 |
|
OneToMany | |||
Sea Squirt (Ciona savignyi) |
Ascidiacea | -- 31 |
|
OneToMany | |
Sea Vase (Ciona intestinalis) |
Ascidiacea | Cin.7801 30 |
|
SNP ID | Clinical significance and condition | Chr 02 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
639320 | Uncertain Significance: Tatton-Brown-rahman syndrome | 25,248,037(-) | C/T | NON_CODING_TRANSCRIPT_VARIANT,SYNONYMOUS_VARIANT | |
644499 | Uncertain Significance: Tatton-Brown-rahman syndrome | 25,240,315(-) | G/A | MISSENSE_VARIANT,NON_CODING_TRANSCRIPT_VARIANT | |
648721 | Likely Pathogenic: Tatton-Brown-rahman syndrome | 25,235,809(-) | G/A | MISSENSE_VARIANT,NON_CODING_TRANSCRIPT_VARIANT | |
650730 | Uncertain Significance: Tatton-Brown-rahman syndrome | 25,241,581(-) | C/T | MISSENSE_VARIANT,NON_CODING_TRANSCRIPT_VARIANT | |
656461 | Pathogenic: Tatton-Brown-rahman syndrome | 25,239,153(-) | C/T | NONSENSE,NON_CODING_TRANSCRIPT_VARIANT |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
dgv1879n106 | CNV | deletion | 24896259 |
dgv57n68 | CNV | loss | 17160897 |
dgv6740n54 | CNV | gain | 21841781 |
dgv6741n54 | CNV | gain | 21841781 |
esv2573580 | CNV | loss | 19546169 |
esv27729 | CNV | loss | 19812545 |
esv33372 | CNV | loss | 17666407 |
esv3583670 | CNV | loss | 25503493 |
esv988737 | CNV | loss | 20482838 |
nsv1008732 | CNV | loss | 25217958 |
nsv1071582 | CNV | deletion | 25765185 |
nsv455908 | CNV | loss | 19166990 |
nsv474667 | CNV | novel sequence insertion | 20440878 |
nsv581215 | CNV | loss | 21841781 |
nsv581216 | CNV | loss | 21841781 |
nsv581217 | CNV | loss | 21841781 |
nsv581218 | CNV | loss | 21841781 |
nsv581219 | CNV | loss | 21841781 |
nsv581221 | CNV | gain+loss | 21841781 |
nsv581230 | CNV | gain+loss | 21841781 |
nsv581232 | CNV | gain | 21841781 |
nsv828653 | CNV | loss | 20364138 |
Disorder | Aliases | PubMed IDs |
---|---|---|
tatton-brown-rahman syndrome |
|
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heyn-sproul-jackson syndrome |
|
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leukemia, acute myeloid |
|
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sporadic pheochromocytoma/secreting paraganglioma |
|
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myelodysplastic syndrome |
|
|