Methionine Synthase Interacts With the Methionine Adenosyl‐Transferase <scp>MATα2</scp> and the <scp>DNA</scp> Methyltransferase <scp>DNMT3b</scp> in the Nucleus

ABSTRACT Transmethylation reactions, which are crucial for regulating gene expression, require S‐adenosyl‐L‐methionine (SAM) as methyl donor. The substrate for SAM synthesis is methionine, which can be produced by methionine synthase (MS) whose dysfunctions are associated with SAM synthesis alterations despite the presence of methionine in the milieu, suggesting a preferential use of the methionine produced de novo. This highlights the crucial role of MS activity and would imply nuclear import of SAM or MS nuclear localization, allowing protein–protein interactions with the methionine adenosyl‐transferases (MAT) responsible for SAM production. Using subcellular fractions of human cells, biochemical and cellular approaches, including incorporation of 14 C‐methyltetrahydrofolate, here we provide the experimental evidence of MS localization and activity in the nucleus where it interacts with MATα2, the catalytic subunit of MATII, and the methyltransferase DNMT3b. These results support the idea that spatial compartmentalization of one‐carbon metabolism could play a major role in regulating the epigenome.