Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

AbstractDespite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.

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Are STATS Arginine-methylated?

Journal of Biological Chemistry ◽

10.1074/jbc.c400606200 ◽

2005 ◽

Vol 280 (23) ◽

pp. 21700-21705 ◽

Cited By ~ 52

Author(s):

Waraporn Komyod ◽

Uta-Maria Bauer ◽

Peter C. Heinrich ◽

Serge Haan ◽

Iris Behrmann

Keyword(s):

Arginine Methylation ◽

Signaling Cascades ◽

Post Translational Modification ◽

Protein Arginine Methyltransferases ◽

Stat Proteins ◽

Fibrosarcoma Cells ◽

Catalytically Active ◽

Interferon Resistance ◽

Stat Pathway

Transcription factors of the STAT (signal transducer and activator of transcription) family are important in signal transduction of cytokines. They are subject to post-translational modification by phosphorylation on tyrosine and serine residues. Recent evidence suggested that STATs are methylated on a conserved arginine residue within the N-terminal region. STAT arginine methylation has been described to be important for STAT function and loss of arginine methylation was discussed to be involved in interferon resistance of cancer cells. Here we provide several independent lines of evidence indicating that the issue of arginine methylation of STATs has to be reassessed. First, we show that treatment of melanoma and fibrosarcoma cells with inhibitors used to suppress methylation (N-methyl-2-deoxyadenosine, adenosine, dl-homocysteine) had profound and rapid effects on phosphorylation of STAT1 and STAT3 but also on p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Second, we show that anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Third, we show that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) did not methylate STAT proteins, and cotransfection with PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, our data suggest the absence of arginine methylation of STAT1 and STAT3.

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Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4

Biochemical Journal ◽

10.1042/bj20031176 ◽

2004 ◽

Vol 379 (2) ◽

pp. 283-289 ◽

Cited By ~ 47

Author(s):

Marie-Chloé BOULANGER ◽

Tina Branscombe MIRANDA ◽

Steven CLARKE ◽

Marco di FRUSCIO ◽

Beat SUTER ◽

...

Keyword(s):

Rna Binding ◽

Developmental Stages ◽

Rna Binding Proteins ◽

Genetic System ◽

Arginine Methylation ◽

Type I ◽

Protein Arginine Methyltransferases ◽

Arginine Residues ◽

Drosophila Protein

The role of arginine methylation in Drosophila melanogaster is unknown. We identified a family of nine PRMTs (protein arginine methyltransferases) by sequence homology with mammalian arginine methyltransferases, which we have named DART1 to DART9 (Drosophilaarginine methyltransferases 1–9). In keeping with the mammalian PRMT nomenclature, DART1, DART4, DART5 and DART7 are the putative homologues of PRMT1, PRMT4, PRMT5 and PRMT7. Other DART family members have a closer resemblance to PRMT1, but do not have identifiable homologues. All nine genes are expressed in Drosophila at various developmental stages. DART1 and DART4 have arginine methyltransferase activity towards substrates, including histones and RNA-binding proteins. Amino acid analysis of the methylated arginine residues confirmed that both DART1 and DART4 catalyse the formation of asymmetrical dimethylated arginine residues and they are type I arginine methyltransferases. The presence of PRMTs in D. melanogaster suggest that flies are a suitable genetic system to study arginine methylation.

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Exploring the role of post-translational modifications on protein–protein interactions with survivin

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2013.07.027 ◽

2013 ◽

Vol 538 (2) ◽

pp. 64-70 ◽

Cited By ~ 16

Author(s):

Rita Nogueira-Ferreira ◽

Rui Vitorino ◽

Manuel J. Ferreira-Pinto ◽

Rita Ferreira ◽

Tiago Henriques-Coelho

Keyword(s):

Protein Interactions ◽

Protein Protein Interactions ◽

Post Translational Modifications

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Role of Protein Arginine Methyltransferases and Inflammation in Muscle Pathophysiology

Frontiers in Physiology ◽

10.3389/fphys.2021.712389 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hyun-Kyung So ◽

Sunghee Kim ◽

Jong-Sun Kang ◽

Sang-Jin Lee

Keyword(s):

Skeletal Muscle ◽

Chronic Inflammation ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Current Knowledge ◽

Arginine Methylation ◽

Muscle Physiology ◽

Post Translational Modification ◽

Protein Arginine Methyltransferases

Arginine methylation mediated by protein arginine methyltransferases (PRMTs) is a post-translational modification of both histone and non-histone substrates related to diverse biological processes. PRMTs appear to be critical regulators in skeletal muscle physiology, including regeneration, metabolic homeostasis, and plasticity. Chronic inflammation is commonly associated with the decline of skeletal muscle mass and strength related to aging or chronic diseases, defined as sarcopenia. In turn, declined skeletal muscle mass and strength can exacerbate chronic inflammation. Thus, understanding the molecular regulatory pathway underlying the crosstalk between skeletal muscle function and inflammation might be essential for the intervention of muscle pathophysiology. In this review, we will address the current knowledge on the role of PRMTs in skeletal muscle physiology and pathophysiology with a specific emphasis on its relationship with inflammation.

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Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation

Nucleic Acids Research ◽

10.1093/nar/gku705 ◽

2014 ◽

Vol 42 (15) ◽

pp. 9908-9924 ◽

Cited By ~ 23

Author(s):

Jen-Hao Yang ◽

Yi-Ying Chiou ◽

Shu-Ling Fu ◽

I-Yun Shih ◽

Tsai-Hsuan Weng ◽

...

Keyword(s):

Dna Damage ◽

Rna Processing ◽

Tumor Development ◽

Arginine Methylation ◽

Wild Type ◽

Post Translational Modifications ◽

Heterogeneous Nuclear Ribonucleoprotein ◽

Damage Response ◽

Nuclear Ribonucleoprotein

Abstract Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA-binding protein involved in chromatin remodeling, RNA processing and the DNA damage response. In addition, increased hnRNPK expression has been associated with tumor development and progression. A variety of post-translational modifications of hnRNPK have been identified and shown to regulate hnRNPK function, including phosphorylation, ubiquitination, sumoylation and methylation. However, the functional significance of hnRNPK arginine methylation remains unclear. In the present study, we demonstrated that the methylation of two essential arginines, Arg296 and Arg299, on hnRNPK inhibited a nearby Ser302 phosphorylation that was mediated through the pro-apoptotic kinase PKCδ. Notably, the engineered U2OS cells carrying an Arg296/Arg299 methylation-defective hnRNPK mutant exhibited increased apoptosis upon DNA damage. While such elevated apoptosis can be diminished through addition with wild-type hnRNPK, we further demonstrated that this increased apoptosis occurred through both intrinsic and extrinsic pathways and was p53 independent, at least in part. Here, we provide the first evidence that the arginine methylation of hnRNPK negatively regulates cell apoptosis through PKCδ-mediated signaling during DNA damage, which is essential for the anti-apoptotic role of hnRNPK in apoptosis and the evasion of apoptosis in cancer cells.

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The Role of Low Complexity Regions in Protein Interaction Modes: An Illustration in Huntingtin

International Journal of Molecular Sciences ◽

10.3390/ijms22041727 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1727

Author(s):

Kristina Kastano ◽

Pablo Mier ◽

Miguel A. Andrade-Navarro

Keyword(s):

Protein Interaction ◽

Protein Interactions ◽

Structural Information ◽

Low Complexity ◽

Protein Interaction Data ◽

Protein Protein Interactions ◽

Post Translational Modifications ◽

Evolutionarily Conserved ◽

And Function

Low complexity regions (LCRs) are very frequent in protein sequences, generally having a lower propensity to form structured domains and tending to be much less evolutionarily conserved than globular domains. Their higher abundance in eukaryotes and in species with more cellular types agrees with a growing number of reports on their function in protein interactions regulated by post-translational modifications. LCRs facilitate the increase of regulatory and network complexity required with the emergence of organisms with more complex tissue distribution and development. Although the low conservation and structural flexibility of LCRs complicate their study, evolutionary studies of proteins across species have been used to evaluate their significance and function. To investigate how to apply this evolutionary approach to the study of LCR function in protein–protein interactions, we performed a detailed analysis for Huntingtin (HTT), a large protein that is a hub for interaction with hundreds of proteins, has a variety of LCRs, and for which partial structural information (in complex with HAP40) is available. We hypothesize that proteins RASA1, SYN2, and KAT2B may compete with HAP40 for their attachment to the core of HTT using similar LCRs. Our results illustrate how evolution might favor the interplay of LCRs with domains, and the possibility of detecting multiple modes of LCR-mediated protein–protein interactions with a large hub such as HTT when enough protein interaction data is available.

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Inhibiting Arginine Methylation as a Tool to Investigate Cross-Talk with Methylation and Acetylation Post-Translational Modifications in a Glioblastoma Cell Line

Proteomes ◽

10.3390/proteomes6040044 ◽

2018 ◽

Vol 6 (4) ◽

pp. 44 ◽

Cited By ~ 3

Author(s):

Sabrina Samuel ◽

Alistair Marsden ◽

Srihari Deepak ◽

Francisco Rivero ◽

John Greenman ◽

...

Keyword(s):

Cell Viability ◽

Cell Line ◽

Cross Talk ◽

3D Models ◽

Arginine Methylation ◽

Post Translational Modifications ◽

Protein Arginine Methyltransferases ◽

Average Survival ◽

Common Grade ◽

2D And 3D

Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known as protein arginine methyltransferases (PRMT1-9) can lead to mono- or di-ArgMe, and in the latter case symmetric or asymmetric dimethylation (SDMA and ADMA, respectively). Using the most common GBM cell line, we have profiled the expression of PRMTs, used ArgMe inhibitors as tools to investigate post-translational modifications cross-talk and measured the effect of ArgMe inhibitors on cell viability. We have identified novel SDMA events upon inhibition of ADMA in GBM cells and spheroids. We have observed cross-talk between ADMA and lysine acetylation in GBM cells and platelets. Treatment of GBM cells with furamidine, a PRMT1 inhibitor, reduces cell viability in 2D and 3D models. These data provide new molecular understanding of a disease with unmet clinical needs.

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Cross-talk among epigenetic modifications: lessons from histone arginine methylation

Biochemical Society Transactions ◽

10.1042/bst20130003 ◽

2013 ◽

Vol 41 (3) ◽

pp. 751-759 ◽

Cited By ~ 55

Author(s):

Diego Molina-Serrano ◽

Vassia Schiza ◽

Antonis Kirmizis

Keyword(s):

Cross Talk ◽

Influence Factor ◽

Arginine Methylation ◽

Epigenetic Modifications ◽

Post Translational Modifications ◽

Protein Arginine Methyltransferases ◽

Chromatin States ◽

Control Gene Expression ◽

Functional States ◽

Histone Arginine Methylation

Epigenetic modifications, including those occurring on DNA and on histone proteins, control gene expression by establishing and maintaining different chromatin states. In recent years, it has become apparent that epigenetic modifications do not function alone, but work together in various combinations, and cross-regulate each other in a manner that diversifies their functional states. Arginine methylation is one of the numerous PTMs (post-translational modifications) occurring on histones, catalysed by a family of PRMTs (protein arginine methyltransferases). This modification is involved in the regulation of the epigenome largely by controlling the recruitment of effector molecules to chromatin. Histone arginine methylation associates with both active and repressed chromatin states depending on the residue involved and the configuration of the deposited methyl groups. The present review focuses on the increasing number of cross-talks between histone arginine methylation and other epigenetic modifications, and describe how these cross-talks influence factor binding to regulate transcription. Furthermore, we present models of general cross-talk mechanisms that emerge from the examples of histone arginine methylation and allude to various techniques that help decipher the interplay among epigenetic modifications.

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The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma

Epigenomes ◽

10.3390/epigenomes5010002 ◽

2021 ◽

Vol 5 (1) ◽

pp. 2

Author(s):

Tanner Wright ◽

Yalong Wang ◽

Mark T. Bedford

Keyword(s):

Hepatocellular Carcinoma ◽

Staphylococcal Nuclease ◽

Arginine Methylation ◽

Effector Protein ◽

Cancer Type ◽

Post Translational Modification ◽

Protein Arginine Methyltransferases ◽

Disease Phenotypes ◽

Tudor Domain

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.

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Role of small nuclear RNAs in eukaryotic gene expression

Essays in Biochemistry ◽

10.1042/bse0540079 ◽

2013 ◽

Vol 54 ◽

pp. 79-90 ◽

Cited By ~ 34

Author(s):

Saba Valadkhan ◽

Lalith S. Gunawardane

Keyword(s):

Gene Expression ◽

Protein Interactions ◽

Rna Stability ◽

Splice Sites ◽

Branch Site ◽

Small Nuclear Rnas ◽

Eukaryotic Gene Expression ◽

Eukaryotic Gene ◽

Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

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