Cell cycle regulation by the PRMT6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors.
PRMT6 belongs to the family of Protein Arginine Methyltransferase (PRMT) enzymes that catalyze the methylation of guanidino nitrogens of arginine residues. PRMT6 has been shown to modify the tail of histone H3, but the in vivo function of PRMT6 is largely unknown. Here, we show that PRMT6 regulates cell cycle progression. Knockdown of PRMT6 expression in the human osteosarcoma cell line U2OS results in an accumulation of cells at the G2 checkpoint. Loss of PRMT6 coincides with upregulation of p21 and p27, two members of the CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors. Gene expression and promoter analysis show that p21 and p27 are direct targets of PRMT6, which involves methylation of arginine-2 of histone H3. Our findings imply arginine methylation of histones by PRMT6 in cell cycle regulation.
Department of Molecular Cancer Research and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Markus A
MA
Kleinschmidt
Petra
P
de Graaf
Hetty A A M
HA
van Teeffelen
H Th Marc
HT
Timmers
D055162:Biocatalysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D014158:Transcription, Genetic
C493956:CDKN1A protein, human; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases