Protein arginine methyltransferases: promising targets for cancer therapy

Abstract

Protein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.

Fig. 1. Protein arginine methylation and responsible enzymes.

a The mammalian PRMT family. Nine PRMTs were identified, and these have unique signatures (dark blue lines) with high sequence similarity (a, Motif I: VLD/EVGXGXG; b, Post-I: V/IXG/AXD/E; c, Motif II: F/I/VDI/L/K; d, Motif III: LR/KXXG; e, THW loop). Their enzymatic types and cellular localization are shown. b Types of arginine methylation. The arginine residue has two equivalent nitrogen atoms in its guanidino group. Types I, II, and III PRMTs generate monomethyl arginine (MMA) marks. The subsequent generation of asymmetric dimethyl arginine (ADMA) is catalyzed by type I enzymes (PRMT1, PRMT2, PRMT3, CARM1, PRMT6, and PRMT8), and symmetric dimethyl arginine (SDMA) is produced by type II enzymes (PRMT5 and PRMT9). PRMT7, a type III enzyme, generates only MMA.

Fig. 2. Biological functions of protein arginine methylation.

Protein arginine methylation is observed in both histones and nonhistone proteins, which contribute to diverse cellular responses for maintaining cellular homeostasis in biological systems. The expression and activity of PRMTs are regulated by developmental and pathogenic processes, genetic mutations, and various environmental factors.

Fig. 3. Regulation of the cell cycle through protein arginine methylation.

The cell cycle is mainly regulated by phase-specific oscillation of cyclin-dependent kinase (CDK)-cyclin complexes. The expression of several cyclins (Cyclin E, Cyclin D1, etc.) and CDKs is epigenetically regulated by PRMTs (not shown). CDK4 is directly methylated by PRMT1, which inhibits binding with Cyclin D and blocks cell cycle progression. In contrast, methylation of E2F1 by either PRMT1 or PRMT5 results in cell progression from G1 to S phase. Several CKIs (CDK inhibitors), such as p16, p21, and p27, are directly methylated by PRMTs to regulate their binding with CDK-cyclin complexes or their cellular localization. During mitosis, PRMT6-mediated H3R2me2a recruits Aurora B kinase into chromosomes along with CPC components, enabling H3S10 phosphorylation. Another CPC component, INCENP, is also methylated by PRMT1, which promotes its interaction with Aurora B kinase. Together, the activities of PRMT1 and PRMT6 during M phase are required for chromosome condensation and proper segregation.

Fig. 4. Regulation of the DNA damage response through protein arginine methylation.

Under DNA double-strand breaks, the MRE11–RAD50–NBS1 complex is recruited into the DNA lesion and activates ATM/CHK2 kinase signaling. PRMT1-mediated MRE11 methylation is essential for exonuclease activity and localization to DNA. There are two main repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ). 53BP1, a major regulator of NHEJ, is competitively methylated by PRMT1 and PRMT5 in the GAR motif. PRMT1-mediated methylation of 53BP1 promotes DNA binding (not shown), and PRMT5-mediated methylation increases the stability of 53BP1, which contributes to NHEJ repair. BRCA1, a well-established key regulator of HR, is methylated by PRMT1, but its role is unknown. Arginine methylation of RUVBL1 (a cofactor of the TIP60 complex) by PRMT5 facilitates TIP60α-dependent histone H4 Lys16 acetylation (H4K16ac), which blocks 53BP1 recruitment to reinforce HR.