epigenomes Review The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma Tanner Wright 1,2, Yalong Wang 1 and Mark T. Bedford 1,* 1 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; [email protected] (T.W.); [email protected] (Y.W.) 2 Graduate Program in Genetics & Epigenetics, UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA * Correspondence: [email protected] Abstract: Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor domain- containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy. Keywords: arginine methylation; PRMT5; SND1; Tudor-SN; p100; HCC Citation: Wright, T.; Wang, Y.; Bedford, M.T. The Role of the PRMT5–SND1 Axis in Hepatocellular 1. Introduction Carcinoma. Epigenomes 2021, 5, 2. https://doi.org/10.3390/ Signal transduction is the process by which information is relayed through a cell. epigenomes5010002 Extracellular signals, such as growth factors or contact points with other cells, stimu- late receptors on the cell surface to initiate this process by converting one stimulus (lig- Received: 13 December 2020 and binding) into another (phosphorylation). This signal initiation event is then propelled Accepted: 3 January 2021 through the cytoplasm and into the nucleus using a series of sequential PTM events that Published: 5 January 2021 rely on “reader” proteins, or effector molecules, to dock onto a specific PTM and then promote the deposition of a new PTM downstream, which in turn is read and relayed Publisher’s Note: MDPI stays neu- by another effector. There is a vast array of different PTMs including, but not limited to, tral with regard to jurisdictional clai- phosphorylation, acetylation, ubiquitination and methylation, which can all be read by ms in published maps and institutio- specialized protein domains in effector molecules [1]. These globular domain types include nal affiliations. SH2s (phosphor-tyrosine readers), FHAs/14-3-3s/BRCTs (phosphor-serine/threonine read- ers), Bromo/YEATS domains (acetyl-lysine readers), UBA/UIM/GAT/CUE domains (ubiquitinated-lysine readers), Chromo/PHD/Tudor/BAH domains (methylated-lysine readers), and Tudors (methylated-arginine readers). In this review, we will focus on just Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. one single thread in this hairball of signaling networks: the PRMT5–SND1 axis. This article is an open access article Arginine residues are frequently methylated post-translationally, and these modifi- distributed under the terms and con- cations come in one of three flavors: monomethylarginine (MMA), asymmetric dimethy- ditions of the Creative Commons At- larginine (ADMA), or symmetric dimethylarginine (SDMA) (Figure1). These methyl-mark tribution (CC BY) license (https:// additions occur at the peripheral omega nitrogen of arginine guanidine moieties and creativecommons.org/licenses/by/ are commonly seen at glycine- and arginine-rich (GAR) motifs. Protein arginine methyl- 4.0/). transferases (PRMTs) are the family of nine closely-related enzymes which deposit all Epigenomes 2021, 5, 2. https://doi.org/10.3390/epigenomes5010002 https://www.mdpi.com/journal/epigenomes Epigenomes 2021, 5, x 2 of 23 Epigenomes 2021, 5, 2 2 of 22 and are commonly seen at glycine- and arginine-rich (GAR) motifs. Protein arginine me- thyltransferases (PRMTs) are the family of nine closely-related enzymes which deposit all threethree of these of these marks marks [2]. [There2]. There is a istenth a tenth arginine arginine methyltra methyltransferasensferase called called NDUF NDUFAF7,AF7, whichwhich is not is nota member a member of PRMT of PRMT family, family, and andseems seems to be to a be dedicated a dedicated mitocho mitochondrialndrial en- en- zymezyme [3]. [PRMT13]. PRMT1 is the is primary the primary Type Type I PRMT I PRMT,, which which deposit depositss the themajority majority of ADMA of ADMA marksmarks.. Other Other Type Type I PRMTs I PRMTs include include PRMT2, PRMT2, PRMT3, PRMT3, PRMT4/CARM1, PRMT4/CARM1, PRMT6 PRMT6 and and PRMT8.PRMT8. PRMT7 PRMT7 is capable is capable of depositing of depositing only only MMA MMA marks, marks, and andit is itreferred is referred to as to a asType a Type III enzyme.III enzyme. That That leaves leaves the Type the Type II enzymes, II enzymes, which which deposit deposit SDMA SDMA marks. marks. PRMT9 PRMT9 has hasjust just one oneknown known substrate substrate (SAP145) (SAP145) [4], and [4], andNDUFAF7 NDUFAF7 is also is alsodedicated dedicated to just to justone onemitochon- mitochon- drialdrial substrate substrate (NDUFS2) (NDUFS2) [3]. All [3]. the All remaining the remaining proteins proteins marked marked with with SDMA SDMA are thought are thought to beto PRMT5 be PRMT5 substrates. substrates. Arginine Arginine methylation methylation is a isrelatively a relatively abundant abundant PTM PTM and andover over the the yearsyears,, a number a number of studies of studies have have reported reported similar similar rations rations of the of different the different types types of arginine of arginine methylationmethylation in both in both tissue tissue and andcell celllines lines [5–7 []5, –which7], which generally generally breaks breaks down down to 15 to00 1500:3:2:1:3:2:1 for Argininefor Arginine:ADMA:SDMA:MMA.:ADMA:SDMA:MMA. So, approximately So, approximately 0.6% 0.6% of all of arginine all arginine residues residues found found in proteinsin proteins are arginine are arginine methylated. methylated. FigureFigure 1. The 1. ThePRMTs, PRMTs, the marks the marks they they deposit, deposit, and andthe effectors the effectors of those of those marks. marks. PRMT5 PRMT5 and andPRMT9 PRMT9 deposit deposit the SDMA the SDMA mark,mark, in “green”. in “green”. PRMT1 PRMT1-4,-4, 6 and 6 and 8 all 8 deposit all deposit the the ADMA, ADMA, in in“blue”. “blue”. Methyl Methyl groups groups are are highlighted highlighted in in “red”. “red”. The The effec- effectors, tors, or readers, of the methyl marks are Tudor domain-containing proteins. or readers, of the methyl marks are Tudor domain-containing proteins. TudorTudor domain domainss are the are only the onlyglobular globular folds foldsknown known to bind to methylated bind methylated arginine arginine motifs mo- [8]. tifsThis [8 domain]. This domain type was type first was identified first identified in the in Drosophila the Drosophila melanogaster melanogaster TudorTudor protein protein whichwhich contains contains repeating repeating domains domains thatthat are present are present in a innumber a number of other of other proteins proteins in many in many differentdifferent species species [9] [.9 A]. Adetailed detailed understanding understanding of howhow TudorTudor domains domains interact interact with with SDMA SDMAmotifs motifs was was first first gleaned gleaned from from biochemistry biochemistry and and structure structure studies studies involving involving the humanthe humansurvival survival motor motor neuron neuron (SMN) (SMN) protein protein [10,11 [10,11], which], which is mutated is mutated in spinal in spinal muscular muscular atrophy atrophysyndrome. syndrome. All inAll all, in all, eight eight Tudor Tudor domain-containing domain-containing proteins proteins have have been been reported reported to be to bemethyl-arginine methyl-arginine readers. readers. The The vast vast majority majority of methyl-arginineof methyl-arginine readers readers recognize recognize SDMA SDMAmotifs, motifs, including including SMN, SMN, SPF30, SPF30 and, and SND1, SND1, which which are ubiquitouslyare ubiquitously expressed, expressed, and TDRD1,and TDRD1,TDRD2, TDRD TDRD6,2, TDRD6, and TDRD9,and TDRD9, which which are all are germ all germ cell-specific cell-specific proteins. proteins TDRD3. TDRD3 is currently is the only known ADMA motif effector protein that is also ubiquitously expressed (Figure1 ). PRMT5 has emerged as an important player in HCC [12], the fourth leading cause of cancer mortality in the world [13]. This link to HCC is strengthened by the fact that Epigenomes 2021, 5, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/epigenomes Epigenomes 2021, 5, x 3 of 23 currently the only known ADMA motif effector protein that is also ubiquitously expressed Epigenomes 2021, 5, 2 (Figure 1). 3 of 22 PRMT5 has emerged as an important player in