The Biological Function Of Protein Arginine Methyltransferase PRMT5 Methylation

An epigenetic trait is a stable heritable phenotype resulting from changes in a chromosome, without alterations in the DNA sequence. Epigenetic studies include DNA methylation, histone modifications, chromatin remodeling, non-coding RNA regulation, etc. Histone modification occurs mainly on the N-terminal amino acid residues of histone leading to affecting the binding of the effector proteins and the change of the structure of the nucleosome. PRMT5 could symmetrically methylate histone H2A/H4 N-terminal arginine residues so as to modulate chromatin structure and transcription of target genes, and play an important role in cells. PRMT5 can also methylate non-histone protein substrates to regulate cell growth, migration and development, and the assemble of the Golgi apparatus. In this study, we found that PRMT5 can be methylated. Mass spectrometric analysis found that PRMT5 could be methylated at Arg505 in vivo. We constructed both prokaryotic and eukaryotic expression vectors containing either wild type or PRMT5 mutant (R505A), and established K562 stable cell lines. We found that PRMT5 R505A mutation can reduce the PRMT5 enzymatic activity in vivo and in vitro. In terms of cell growth, wild-type PRMT5 cells grow fast whereas mutant PRMT5 cells grow slower significantly. Previous studies have shown that PRMT5 catalyzes histone resulting H4R3me2s which recruits DNA methyltransferase DNMT3A to repress gamma-globin gene expression in K562 cells. This study confirmed that wild-type PRMT5 reduces the level of the gamma-globin gene expression, whereas mutant PRMT5 increases its expression which is similar to that of PRMT5 knockdown cells. We found that PRMT5 R505A didn’t change the interaction with DNMT3A suggesting that methylation at R505 may be not essential for their interaction. Taken together, the methylation of PRMT5 at R505 has an important biological function.