DNA (cytosine-5)-methyltransferase 3A

Such function is to be distinguished from maintenance DNA methylation which ensures the fidelity of replication of inherited epigenetic patterns.

[5][6] While de novo DNA methylation modifies the information passed on by the parent to the progeny, it enables key epigenetic modifications essential for processes such as cellular differentiation and embryonic development, transcriptional regulation, heterochromatin formation, X-inactivation, imprinting and genome stability.

The two accessory proteins stimulate de novo methylation by each of their interactions with the three isoforms that have a functional catalytic domain.

[18] The PWWP motif is within an about 100 amino acid domain that has one area with a significant amount of basic residues (lysines and arginines), giving a positively charged surface that can bind to DNA.

One accessory protein of the complex binds to an acidic patch on the nucleosome core (see top 3B3 in Figure).

The orientation places the first catalytic DNMT (closest to the accessory protein connected to the nucleosome) in an intermediate position (not close to the linker DNA).

De novo methylation is the main recognized activity of DNMT3A, which is essential for processes such as those mentioned in the introductory paragraphs.

[35] In mice, this gene has shown reduced expression in ageing animals causes cognitive long-term memory decline.

[15] In Dnmt3a-/- mice, many genes associated with HSC self-renewal increase in expression and some fail to be appropriately repressed during differentiation.

[36] This suggests abrogation of differentiation in hematopoietic stem cells (HSCs) and an increase in self-renewal cell-division instead.

Indeed, it was found that differentiation was partially rescued if Dnmt3a-/- HSCs experienced an additional Ctnb1 knockdown – Ctnb1 codes for β-catenin, which participates in self-renewal cell division.

[38] DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease.

[39] It has also been found that DNMT3A-mutated cell lines exhibit transcriptome instability, in that they have much more erroneous RNA splicing as compared to their isogenic wildtype counterparts.

This illustrates 5 isoforms of DNMT3A showing the locations of the PWWP domain, the ADD domain and the catalytic or catalytic-like domains.
DNMTs such as DNMT3A2, with a functioning catalytic domain, require an accessory protein, such as DNMT3B3 without a functioning catalytic domain, for methylating activity in vivo, as in the heterotetrameric structure shown here.