Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in the folate cycle, catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Methionine serves as the precursor of the active methyl donor S-adenosylmethionine, which provides methyl groups for many biological methylations. It has been reported that MTHFR is highly phosphorylated under unperturbed conditions and T34 is the priming phosphorylation

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... ite. In this report, we generated a phospho-specific antibody that recognized T34-phosphorylated form of MTHFR and revealed that MTHFR was phosphorylated at T34 in vivo and this phosphorylation peaked during mitosis. We further demonstrated that the cyclin-dependent kinase 1 (CDK1)/Cyclin B1 complex is the kinase that mediates MTHFR phosphorylation at T34 and the MTHFR immunocomplex purified from mitotic cells exhibited lower enzymatic activity. Inhibition of MTHFR expression resulted in a decrease of H3K9me3 levels, and an increase of transcription of the centromeric heterochromatin markers. Taken together, our results demonstrated that CDK1/Cyclin B1 phosphorylates MTHFR on T34 and MTHFR plays a role in the heterochromatin maintenance at the centromeric region.