DNMT3A

DNMT3A stands for DNA (cytosine-5)-methyltransferase 3 alpha, a DNA methyltransferase that establishes de novo methylation patterns at CpG dinucleotides. It is one of the DNMT3 family members alongside DNMT3B and the catalytically inactive DNMT3L. The DNMT3A gene is located on chromosome 2p23.3 and encodes a nuclear enzyme broadly expressed in developing and adult tissues.

DNMT3A contains an N-terminal regulatory region with a PWWP domain and an ADD domain and a C-terminal catalytic DNA methyltransferase domain. The enzyme transfers a methyl group from S-adenosyl-L-methionine to cytosine, creating 5-methylcytosine. It functions primarily in de novo methylation during development and differentiation, whereas maintenance methylation is largely carried out by DNMT1.

Biological role: DNMT3A shapes the epigenetic landscape during embryogenesis and cellular differentiation. It cooperates with DNMT3L and interacts with histone marks to guide methylation. It also plays a role in hematopoietic stem cell function and lineage specification. Dysregulation can affect imprinting and transposable element silencing.

Clinical significance: Somatic DNMT3A mutations are among the most frequent alterations in acute myeloid leukemia and in clonal hematopoiesis of indeterminate potential. A common hotspot is arginine 882 (R882); such mutations reduce methyltransferase activity and alter methylation patterns, with implications for prognosis and therapy. Germline DNMT3A mutations cause Tatton-Brown-Rahman syndrome, characterized by postnatal overgrowth, macrocephaly, distinctive facial features, and variable intellectual disability.

Therapeutic context: DNA methyltransferase inhibitors such as azacitidine and decitabine are used in hematologic cancers and act by inhibiting DNMT activity, including DNMT3A in affected cells. Ongoing research seeks more selective approaches.