MTHFR promotes heterochromatin maintenance.
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 site. 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.
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China.
Bingtao
B
Zhu
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China.
Zhikai
Z
Xiahou
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China.
Heyu
H
Zhao
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China.
Bin
B
Peng
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China.
Hongchang
H
Zhao
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing 100048, China. Electronic address: Xingzhi_Xu@mail.cnu.edu.cn.
Xingzhi
X
Xu
D000918:Antibody Specificity; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002460:Cell Line; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D042822:Genomic Instability; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006570:Heterochromatin / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation
C534699:CCNB1 protein, human; D056744:Cyclin B1; D006570:Heterochromatin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016203:CDC2 Protein Kinase
CDK1/Cyclin B1; Heterochromatin; MTHFR; Mitosis; Phosphorylation