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CARM1-mediated methylation of protein arginine methyltransferase 5 represses human gamma-globin gene expression in erythroleukemia cells


Nie, M; Wang, Y; Guo, C; Li, X; Deng, Y; Yao, B; Gui, T; Ma, C; Liu, M; Wang, P; Wang, R; Tan, R; Fang, M; Chen, B; He, Y; Huang, DCS; Ju, J; Zhao, Q
2018-09-26
Journal of Biological Chemistry
Journal Article
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 K562 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 gamma-globin gene promoter, and increased the expression of the gamma-globin gene in K562 cells. Moreover, CARM1 knockdown consistently reduced PRMT5 activity and activated gamma-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 gamma-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 gamma-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.
Cancer and Haematology
10.1074/jbc.RA118.004028
30257864
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