Global analysis of protein arginine methylation

Zhang, Fangrong; Kerbl-Knapp, Jakob; Colman, Maria J. Rodríguez; Meinitzer, Andreas; Macher, Therese; Vujić, Nemanja; Fasching, Sandra; Jany-Luig, Evelyne; Korbelius, Melanie; Kuentzel, Katharina B.; Mack, Maximilian; Akhmetshina, Alena; Pirchheim, Anita; Paar, Margret; Rinner, Beate; Hörl, Gerd; Steyrer, Ernst; Stelzl, Ulrich; Burgering, Boudewijn M.T.; Eisenberg, Tobias; Pertschy, Brigitte; Kratky, Dagmar; Madl, Tobias

doi:10.1016/j.crmeth.2021.100016

Cited by 34 publications

(52 citation statements)

References 110 publications

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“…It has been previously found that methylation of FUS RGG3PY by PRMT1 generates asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) by adding two or one methyl group, respectively, to one of the nitrogen atoms of the arginine guanidinium group [ 38 ]. Here, we observed the ADMA/MMA methyl protons as additional peaks in the 1 H NMR spectra ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

Lenard

Zhou

Madreiter‐Sokolowski

et al. 2022

Cells

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Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds found in a variety of plants, can directly interact with amyloidogenic proteins, prevent the formation of toxic aggregates, and in turn play neuroprotective roles. Besides harboring amyloidogenic domains, several proteins involved in NDs possess arginine-glycine/arginine-glycine-glycine (RG/RGG) regions that contribute to the formation of protein condensates. Here, we aimed to assess whether epigallocatechin gallate (EGCG) can play a role in neuroprotection via direct interaction with such RG/RGG regions. We show that EGCG directly binds to the RG/RGG region of fused in sarcoma (FUS) and that arginine methylation enhances this interaction. Unexpectedly, we found that low micromolar amounts of EGCG were sufficient to restore RNA-dependent condensate formation of methylated FUS, whereas, in the absence of EGCG, no phase separation could be observed. Our data provide new mechanistic roles of EGCG in the regulation of phase separation of RG/RGG-containing proteins, which will promote understanding of the intricate function of EGCG in cells.

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Section: Resultsmentioning

confidence: 99%

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

Lenard

Zhou

Madreiter‐Sokolowski

et al. 2022

Cells

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“…Phosphorylation thus acts as a rapid switch, quickly modulating protein function in response to signals ( Hofweber and Dormann, 2019 ). In contrast, transfer of methyl groups to arginine residues catalysed by protein-arginine methyltransferases is a much slower process ( Zhang et al, 2021 ), and whether this modification can be reversed (and which enzyme catalyses demethylation reaction) remains until now poorly understood ( Guccione and Richard, 2019 ). Arginine methylation is therefore significantly more stable and static compared to serine phosphorylation ( Zhang et al, 2021 ), which can be erased within minutes ( Gelens and Saurin, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, transfer of methyl groups to arginine residues catalysed by protein-arginine methyltransferases is a much slower process ( Zhang et al, 2021 ), and whether this modification can be reversed (and which enzyme catalyses demethylation reaction) remains until now poorly understood ( Guccione and Richard, 2019 ). Arginine methylation is therefore significantly more stable and static compared to serine phosphorylation ( Zhang et al, 2021 ), which can be erased within minutes ( Gelens and Saurin, 2018 ). Consequently, we hypothesize that phosphorylation of CIRBP-RGG offers a means of dynamic regulation of its phase separation in vitro , SG association, and protein-protein interactions (e.g.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation Regulates CIRBP Arginine Methylation, Transportin-1 Binding and Liquid-Liquid Phase Separation

Lenard

Hutten

Zhou

et al. 2021

Front. Mol. Biosci.

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Arginine-glycine(-glycine) (RG/RGG) regions are highly abundant in RNA-binding proteins and involved in numerous physiological processes. Aberrant liquid-liquid phase separation (LLPS) and stress granule (SGs) association of RG/RGG regions in the cytoplasm have been implicated in several neurodegenerative disorders. LLPS and SG association of these proteins is regulated by the interaction with nuclear import receptors, such as transportin-1 (TNPO1), and by post-translational arginine methylation. Strikingly, many RG/RGG proteins harbour potential phosphorylation sites within or close to their arginine methylated regions, indicating a regulatory role. Here, we studied the role of phosphorylation within RG/RGG regions on arginine methylation, TNPO1-binding and LLPS using the cold-inducible RNA-binding protein (CIRBP) as a paradigm. We show that the RG/RGG region of CIRBP is in vitro phosphorylated by serine-arginine protein kinase 1 (SRPK1), and discovered two novel phosphorylation sites in CIRBP. SRPK1-mediated phosphorylation of the CIRBP RG/RGG region impairs LLPS and binding to TNPO1 in vitro and interferes with SG association in cells. Furthermore, we uncovered that arginine methylation of the CIRBP RG/RGG region regulates in vitro phosphorylation by SRPK1. In conclusion, our findings indicate that LLPS and TNPO1-mediated chaperoning of RG/RGG proteins is regulated through an intricate interplay of post-translational modifications.

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“…A wealth of studies in recent years has revealed that arginine methylation is as prevalent and versatile as serine phosphorylation and lysine ubiquitylation [ 34 , 35 , 36 , 37 ]. In mammals, a family of nine proteins called protein arginine methyltransferases (PRMTs) catalyzes the transfer of a methyl group from the donor S-adenosylmethionine (SAM) to the guanidino nitrogen atoms of arginine, which generates three forms of methylarginine: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA).…”

Section: Introductionmentioning

confidence: 99%

The Role of Protein Arginine Methyltransferases in DNA Damage Response

Brobbey

Liu

Yin

et al. 2022

IJMS

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In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.

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Global analysis of protein arginine methylation

Cited by 34 publications

References 110 publications

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

Phosphorylation Regulates CIRBP Arginine Methylation, Transportin-1 Binding and Liquid-Liquid Phase Separation

The Role of Protein Arginine Methyltransferases in DNA Damage Response

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