Figures & data
Figure 1. Types of arginine protein methylation.
Types I, II, and III protein arginine methyltransferases (PRMTs) produce monomethylated arginine (MMA) on a guanidino nitrogen atom using S-adenosyl-L-methionine (SAM) as a methyl donor. After the reaction, S-adenosyl-L-homocysteine (SAH) is released, and the formation of asymmetric dimethylated arginine (ADMA) is catalyzed by Type I PRMTs (PRMT1-4, 6, and 8), whereas symmetric dimethylated arginine (SDMA) is catalyzed by Type II enzymes (PRMT5, 7, 9). Additionally, PRMT7 functions as a Type III enzyme. Type III enzymes monomethylate instead of dimethylating the arginine residues on the protein substrates. This figure is adapted from [Citation9].
Figure 2. Model for miRNAs biogenesis.
The biogenesis of miRNAs occurs through 6 general steps [Citation1]. Transcription: miRNA genes are initially transcribed by RNA polymerase II (Pol II) as primary-miRNAs (pri-miRNAs) transcripts (hundreds of nucleotides), which has an imperfectly double-strand region with a hairpin structure where miRNA sequences are embedded [Citation2]. Cleavage and A tailing: A nuclear RNase III named Drosha cleaves the stem-loop of pri-miRNAs to generate the precursor miRNAs (pre-miRNAs, about 60 nucleotides) [Citation3]. Export: pre-miRNAs are exported from the nucleus to the cytoplasm by Exportin-5 [Citation4]. Dicing: Dicer cleaves pre-miRNAs and generates a miRNA/miRNA* duplex (about 20 nucleotides) in the cytoplasm. The miRNA/miRNA* duplex is made up of a biologically active strand called miRNA, which is usually converted into a mature RNA, and an inactive form called miRNA*, which is a “carrier” miRNA that is usually degraded during processing into a mature RNA [Citation5]. Production of mature miRNAs: The miRNA/miRNA* duplex is incorporated in the RNA-induced silencing complex (RISC) which acts to load and unwind genes [Citation6]. Targeting of mRNAs: One miRNA strand (miRNA*) degrades and the other mature strand (miRNA) guides RISC complex to target mRNAs in order to inhibit their expression [Citation9]. This figure is adapted from [Citation13].
Figure 3. Mechanisms of interaction between miRNAs and PRMTs.
Multiple mechanisms of interaction between miRNAs and PRMTs including, a. Regulation of miRNAs by PRMTs in which histones in the promoter regions of miRNAs are methylated such as H3R8me2s, H4R3me2s, etc. resulting in transcriptional silencing of these miRNAs; b. Regulation of PRMTs by miRNAs involves targeting of 3ʹ-UTRs of PRMTs for degradation, ultimately blocking translation of the PRMT protein; c. Example of the reciprocal interplay between PRMTs and miRNAs at multiple levels in normal and cancerous states: during physiologically normal conditions, (I) miRNAs target PRMTs at their 3ʹ-UTRs for degradation, keeping their levels in check. However, in cancer, decrease of miRNA levels via epigenetic mechanisms including (II) PRMT-catalyzed methylation of histones at the promoters of miRNAs can act to silence these same miRNAs. (III) Additionally, PRMTs can methylate proteins of the miRNA processing machinery such as Drosha, which results in deregulation of miRNA biogenesis. Furthermore, another level of complexity is introduced when (IV) certain regulatory loops involve other epigenetic components such as HDACs which can form repressive complexes to further suppress miRNA expression. The net effect is upregulation of PRMTs that promote cancer processes.
Table 1. List of known interplay between PRMTs and miRNAs in cancer.
Table 2. List of known interplay between PRMTs and miRNAs in other conditions.