Protein arginine methyltransferase 5-Methylosome protein 50 complex (PRMT5-MEP50)

The Protein arginine methyltransferase 5-Methylosome protein 50 (PRMT5-MEP50) complex is a type II methyltransferase that catalyzes the symmetric dimethylation of arginine (SDMA) residues on various protein substrates, including histones H4R3, H3R8, and H2AR3 (UniProt P55851). The complex consists of the catalytic PRMT5 subunit and the regulatory MEP50 (WDR77) subunit, which serves as a scaffold to stabilize the complex and facilitate substrate binding (PubMed: 17500065). It plays a critical role in essential cellular functions such as pre-mRNA splicing, DNA damage response, and cell cycle progression (PubMed: 22367201). In many cancers, the PRMT5-MEP50 complex is overexpressed, leading to the silencing of tumor suppressor genes and the promotion of oncogenic pathways (PubMed: 26076306). A significant therapeutic opportunity exists in MTAP-deleted tumors, where the accumulation of the metabolite MTA allows for the use of MTA-cooperative inhibitors that selectively target the PRMT5-MEP50 complex in malignant cells (PubMed: 26912361). Clinical development of PRMT5 inhibitors has targeted a variety of solid and hematological malignancies, though challenges such as dose-limiting hematological toxicities remain (PubMed: 33067308). Additionally, the complex is being investigated as a target for sickle cell disease due to its role in repressing fetal hemoglobin (PubMed: 21572428). Pharmacological inhibition of this complex aims to restore normal gene expression and induce cell cycle arrest or apoptosis in tumor cells (PubMed: 35173151).

Other names

PRMT5-WDR77 complexJBP1-MEP50 complexSKB1-MEP50 complexMethylosome complex

Inhibition of the symmetric dimethylation of arginine residues on histone and non-histone proteins by competing with the cofactor S-adenosylmethionine (SAM) or by cooperatively binding with methylthioadenosine (MTA) in MTAP-deficient cells (PubMed: 35173151).