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 histone 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, which demonstrates 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 therapeutic targeting of PRMT5.

Figure 1

PRMT5-induced epigenetic and post-translational changes have a significant impact on cell growth and proliferation. Through multiple interactions with specific transcription factors and chromatin-modifying enzymes, PRMT5 is capable of controlling critical cellular pathways. (a) PRMT5 associates with specific ATP-dependent chromatin remodelers, co-repressors as well as co-activators, and controls expression of key target genes involved in growth control, metastasis, differentiation and development. (b) PRMT5 alone or in combination with MEP50 interacts with a variety of transcriptional regulators to epigenetically modify specific histone arginine residues including H3R8 and H4R3, and to induce gene silencing. PRMT5-induced H4R3 methylation orchestrates recruitment of repressor DNA methyltransferase DNMT3A. PRMT5 also promotes transcriptional silencing by post-translationally modifying chromatin-binding proteins such as MBD2, p53 and CBP, and altering their biochemical properties.

Figure 2

Role of PRMT5 in cell signaling and organelle biogenesis. Association of PRMT5 with various receptors, signaling molecules and organelle subunits allows it to impact cell proliferation, tumorigenesis and cell death. (a) PRMT5 targets multiple proteins in the cytoplasm and modulates signaling pathways, RNA processing, and organelle assembly. (b) Methylation of EGFR by PRMT5 has an inhibitory effect on ERK signaling and affects cellular proliferation, migration and invasion, while interaction of PRMT5 with death receptors DR4 and DR5 leads to inhibition of TRAIL-mediated apoptosis and induction of pro-survival gene expression. In the context of pluripotent stem cells, phosphorylation of PRMT5 by oncogenic JAK kinase mutants results in loss of its methyltransferase activity, and hyperproliferation of hematopoietic stem cells. Through its ability to interact with and methylate various cytoplasmic proteins, PRMT5 is also involved in assembly of spliceosomal proteins, Golgi apparatus, and the 40S ribosomal subunit.