Versatility of PRMT5-induced methylation in growth control and development

Abstract

Arginine methylation governs important cellular processes that impact growth and proliferation, as well as differentiation and development. Through their ability to catalyze symmetric or asymmetric methylation of histones and non-histone proteins, members of the protein arginine methyltransferase (PRMT) family regulate chromatin structure and expression of a wide spectrum of target genes. Unlike other PRMTs, PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing. Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways, demonstrating its versatility as an enzyme involved in both epigenetic regulation of anti-cancer target genes and organelle biogenesis. These studies not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control, but also justify targeting PRMT5 therapeutically.

Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

“…Methyltransferase Activity-PRMT5 plays roles both in the nucleus and in the cytoplasm and has various substrates, including histones, cytoplasmic signal transducers, spliceosomal proteins, transcription factors, and PIWI proteins (49). In the context of transcriptional regulation, histones are particularly well known targets of PRMT5-directed methylation (39,50,51).…”

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

“…Protein arginine methyltransferases (PRMTs) are classified as type 1 and type 2 enzymes on the basis of their ability to catalyze the formation of asymmetric and symmetric dimethyl arginine, respectively. PRMT5 is the major type 2 enzyme identified thus far, which, together with its cofactor MEP50, mediates the methylation of histones H2A and H4 at R3 and histone H3 at R8 (9). The symmetric dimethylation of these histone residues generally generates repressive marks for gene transcription, and PRMT5 has been found in several transcriptional repressor complexes, including those containing SIN3A/HDAC, MBD2/NURD, and N-CoR/SMRT (9).…”

Novel Mechanism of Negative Regulation of 1,25-Dihydroxyvitamin D3-induced 25-Hydroxyvitamin D3 24-Hydroxylase (Cyp24a1) Transcription

“…In addition, it has been shown that ATP-dependent chromatin remodeling complexes can act together with histone-modifying enzymes to modulate transcription (18 -20). Among the histone-modifying enzymes are the protein-arginine methyltransferases (PRMTs) that have been implicated in transcriptional activation or repression (21)(22)(23)(24). Both type I and type II PRMTs catalyze the formation of monomethylarginine.…”

“…Transfer of an additional methyl group results in the formation of asymmetrically dimethylated arginines (catalyzed by type I enzymes) or symmetrically dimethylated arginines (catalyzed by type II enzymes). PRMT4 (CARM1), a type I PRMT, methylates arginines 2, 17, and 26 of histone 3 and is associated with transcriptional activation, whereas PRMT5, a type II PRMT, has been linked to gene silencing through repressive histone marks including symmetrical dimethylation of H3R8 and H4R3 (21)(22)(23)(24). Little is known about the role of SWI/SNF and PRMTs in VDR-mediated transcription.…”

“…One of the most pronounced effects of 1,25(OH) 2 D 3 is increased synthesis of 25-hydroxyvitamin D 3 24-hydroxylase (CYP24A1), the enzyme that accelerates the catabolism of 1,25(OH) 2 D 3 (25). Thus, by inducing CYP24A1, 1,25(OH) 2 D 3 regulates its own synthesis, protecting against hypercalcemia.…”