DNA (Cytosin-5)-Methyltransferase 3A

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process known as DNA methylation. In humans, the enzyme is encoded by the DNMT3A gene.

DNA (cytosine-5)-methyltransferase 3A is responsible for de novo DNA methylation. This function must be distinguished from maintenance DNA methylation, which ensures the replication of inherited epigenetic patterns. DNA (cytosine-5)-methyltransferase 3A belongs to the family of DNA methyltransferase enzymes, which consists of the protagonists DNA (cytosine-5)-methyltransferase 1 (DNMT1), DNA (cytosine-5)-methyltransferase 3A (DNMT3A) and DNA (cytosine-5)-methyltransferase 3b (DNMT3B).

De novo DNA methylation" modifies the genetic information passed on from parents to offspring. This enables important epigenetic modifications that are essential for processes such as cell differentiation and embryonic development, transcription regulation, heterochromatin formation, X-inactivation, imprinting and genome stability.

The coding gene, the DNMT3a gene, is the most commonly mutated gene in clonal hematopoiesis, a common age-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell precursors contribute to the formation of a genetically distinct subpopulation of blood cells.

There are two main protein isoforms, DNMT3A1 and DNMT3A2, with molecular weights of approximately 130 kDa and 100 kDa, respectively. The DNMT3A2 protein, which lacks the N-terminal region of DNMT3A1, is encoded by a transcript that is initiated by a downstream promoter. These isoforms are found in different cell types. When it was originally discovered, DNMT3A2 was found to be highly expressed in the testes, ovaries, spleen and thymus. It has also been shown to be induced in the hippocampus of the brain. It is also required in the hippocampus to build up memory. DNMT3A2 is also upregulated in the nucleus accumbens shell in response to cocaine. The catalytic domain (the methyltransferase domain) is highly conserved, even among prokaryotes. The three DNA methyltransferases (DNMT3A1, DNMT3A2 and DNMT3B) catalyze reactions in which a methyl group is attached to a cytosine, usually at a CpG site in DNA. To be effective, these enzymes must interact with an accessory protein (e.g. DNMT3B3, DNMT3L or others). Two accessory proteins (which have no catalytic activity) complexed with two DNMTs with a catalytic domain form a heterotetramer.

Function

DNMT1 is responsible for maintenance DNA methylation, while DNMT3A and DNMT3B are responsible for both maintenance DNA methylation (correcting the errors of DNMT1) and de novo DNA methylation. After DNMT1 was knocked down in human cancer cells, these cells retained their inherited methylation pattern, suggesting maintenance activity of the expressed DNMT3s. DNMT3s show equal affinity for unmethylated and hemimethylated DNA substrates, whereas DNMT1 has a 10-40-fold preference for hemimethylated DNA. DNMT3 can bind to both forms and thus potentially perform both maintenance and de novo modifications. DNMT3A is essential for genetic imprinting.

Research on long-term memory storage in humans suggests that memory is maintained by DNA methylation. In rats in which fear conditioning induces a new, strong long-term memory, the expression of about 1,000 genes is reduced and the expression of about 500 genes is increased in the hippocampus region of the brain. These changes occur 24 hours after training. At this time, the expression of 9.17% of the genome in the rat hippocampus is altered. The reduced expression of genes is associated with de novo methylation of the genes. In mice, reduced expression of this gene has been shown to lead to a deterioration of long-term cognitive memory in aging animals.

Clinical relevance: The DNMT3A gene is frequently mutated in cancer and is one of the 127 frequently mutated genes identified in the Cancer Genome Atlas project. DNMT3A mutations were most frequently observed in acute myeloid leukemia(AML), where they occurred in just over 25% of sequenced cases. These mutations occur most frequently at position R882 in the protein, and this mutation can lead to loss of function. DNMT3A mutations are associated with poor overall survival, suggesting that they have an important joint effect on the potential of AML cells to cause fatal disease. Mutations in this gene are also associated with Tatton-Brown-Rahman syndrome, an overgrowth disorder.

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