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RSS FeedsCARM1-mediated methylation of protein arginine methyltransferase 5 represses human {gamma}-globin gene expression in erythroleukemia cells [DNA and Chromosomes] (Journal of Biological Chemistry)

 
 

11 november 2018 02:00:14

 
CARM1-mediated methylation of protein arginine methyltransferase 5 represses human {gamma}-globin gene expression in erythroleukemia cells [DNA and Chromosomes] (Journal of Biological Chemistry)
 




Protein arginine methyltransferase 5 (PRMT5) is a member of the arginine methyltransferase protein family that critically mediates the symmetric dimethylation of Arg-3 at histone H4 (H4R3me2s) and is involved in many key cellular processes, including hematopoiesis. However, the post-translational modifications (PTMs) of PRMT5 that may affect its biological functions remain less well-understood. In this study, using MS analyses, we found that PRMT5 itself is methylated in human erythroleukemia Lys-562 cells. Biochemical assays revealed that coactivator-associated arginine methyltransferase 1 (CARM1) interacts directly with and methylates PRMT5 at Arg-505 both in vivo and in vitro. Substitutions at Arg-505 significantly reduced PRMT5`s methyltransferase activity, decreased H4R3me2s enrichment at the ?-globin gene promoter, and increased the expression of the ?-globin gene in Lys-562 cells. Moreover, CARM1 knockdown consistently reduced PRMT5 activity and activated ?-globin gene expression. Importantly, we show that CARM1-mediated methylation of PRMT5 is essential for the intracellular homodimerization of PRMT5 to its active form. These results thus reveal a critical PTM of PRMT5 that represses human ?-globin gene expression. We conclude that CARM1-mediated asymmetric methylation of PRMT5 is critical for its dimerization and methyltransferase activity leading to the repression of ?-globin expression. Given PRMT5`s crucial role in diverse cellular processes, these findings may inform strategies for manipulating its methyltransferase activity for managing hemoglobinopathy or cancer.


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28 viewsCategory: Biochemistry
 
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