PRMT5 function and targeting in cancer

Abstract

Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapy-response. Here we discuss the function of PRMT5, a member of the nine-member PRMT family, in controlling oncogenic processes including tumor intrinsic, as well as extrinsic microenvironmental signaling pathways. We discuss PRMT5 effect on histone methylation and methylation of regulatory proteins including those involved in RNA splicing, cell cycle, cell death and metabolic signaling. In all, we highlight the importance of PRMT5 regulation and function in cancer, which provide the foundation for therapeutic modalities targeting PRMT5.

Keywords: MEP50; PRMT1; PRMT5; histone; methylation; methyltransferase; splicing; transcription.

Figure 1. FIGURE 1: PRMT5 methylation of histone tails.

PRMT5 methylation of histone tails results in activation/repression of target gene expression depending on subsequent modifications of histones or DNA.

Figure 2. FIGURE 2: PRMT5 methylation of transcription factors.

PRMT5 methylation of select transcription factors affects their activity, recruitment and stability.

Figure 3. FIGURE 3: PRMT5 effect on splicing machinery.

PRMT5 modification of splicing-machinery components is required for snRNP assembly and alternative splicing in pre-mRNAs, including those with a weak 5′ splice site (A-T rich), ensuring splicing fidelity.

Figure 4. FIGURE 4: Regulation of growth factor receptors by PRMT5.

Arginine methylations of the growth factor receptors EGFR and PDGFR affect ERK and AKT activation, respectively.

Figure 5. FIGURE 5: PRMT5 control of cell cycle and DNA repair.

PRMT5 modify factors controlling cell cycle, thereby facilitating cell cycle checkpoint activation and homologous recombination-based DNA break repair.

Figure 6. FIGURE 6: The pathways regulating PRMT5 in cancer.

The activity, localization and protein-protein interaction are altered by indicated upstream components, posttranslational modification of PRMT5 or its adaptor protein, MEP50. PRMT5 interaction with adaptors serves to identify the substrates which will be methylated. PRMT5 activity is inhibited by the endogenous inhibitor, MTA, an MTAP substrate which is deleted in up to 30% of tumors.