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Protein arginine methylation: from enigmatic functions to therapeutic targeting

Nature Reviews Drug Discovery volume 20, pages 509–530 (2021)Cite this article

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Abstract

Protein arginine methyltransferases (PRMTs) are emerging as attractive therapeutic targets. PRMTs regulate transcription, splicing, RNA biology, the DNA damage response and cell metabolism; these fundamental processes are altered in many diseases. Mechanistically understanding how these enzymes fuel and sustain cancer cells, especially in specific metabolic contexts or in the presence of certain mutations, has provided the rationale for targeting them in oncology. Ongoing inhibitor development, facilitated by structural biology, has generated tool compounds for the majority of PRMTs and enabled clinical programmes for the most advanced oncology targets, PRMT1 and PRMT5. In-depth mechanistic investigations using genetic and chemical tools continue to delineate the roles of PRMTs in regulating immune cells and cancer cells, and cardiovascular and neuronal function, and determine which pathways involving PRMTs could be synergistically targeted in combination therapies for cancer. This research is enhancing our knowledge of the complex functions of arginine methylation, will guide future clinical development and could identify new clinical indications.

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Fig. 1: Distribution and functions of arginine methylated proteins.
Fig. 2: Structural mechanism of PRMT inhibition.

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References

  1. Fuhrmann, J., Clancy, K. W. & Thompson, P. R. Chemical biology of protein arginine modifications in epigenetic regulation. Chem. Rev. 115, 5413–5461 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gayatri, S. & Bedford, M. T. Readers of histone methylarginine marks. Biochim. Biophys. Acta 1839, 702–710 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Guccione, E. & Richard, S. The regulation, functions and clinical relevance of arginine methylation. Nat. Rev. Mol. Cell Biol. 20, 642–657 (2019).

    CAS  PubMed  Google Scholar 

  4. Chong, P. A., Vernon, R. M. & Forman-Kay, J. D. RGG/RG motif regions in RNA binding and phase separation. J. Mol. Biol. 430, 4650–4665 (2018).

    CAS  PubMed  Google Scholar 

  5. Rajyaguru, P. & Parker, R. RGG motif proteins: modulators of mRNA functional states. Cell Cycle 11, 2594–2599 (2012).

    CAS  PubMed  Google Scholar 

  6. Thandapani, P., O’Connor, T. R., Bailey, T. L. & Richard, S. Defining the RGG/RG motif. Mol. Cell 50, 613–623 (2013).

    CAS  PubMed  Google Scholar 

  7. Nott, T. J. et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57, 936–947 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Uversky, V. N. Intrinsically disordered proteins in overcrowded milieu: membrane-less organelles, phase separation, and intrinsic disorder. Curr. Opin. Struct. Biol. 44, 18–30 (2017).

    CAS  PubMed  Google Scholar 

  9. Alberti, S. & Dormann, D. Liquid–liquid phase separation in disease. Annu. Rev. Genet. 53, 171–194 (2019).

    CAS  PubMed  Google Scholar 

  10. Bentmann, E. et al. Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J. Biol. Chem. 287, 23079–23094 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mazroui, R. et al. Trapping of messenger RNA by Fragile X mental retardation protein into cytoplasmic granules induces translation repression. Hum. Mol. Genet. 11, 3007–3017 (2002).

    CAS  PubMed  Google Scholar 

  12. Boisvert, F. M., Cote, J., Boulanger, M. C. & Richard, S. A proteomic analysis of arginine-methylated protein complexes. Mol. Cell Proteom. 2, 1319–1330 (2003).

    CAS  Google Scholar 

  13. Bremang, M. et al. Mass spectrometry-based identification and characterisation of lysine and arginine methylation in the human proteome. Mol. Biosyst. 9, 2231–2247 (2013).

    CAS  PubMed  Google Scholar 

  14. Fong, J. Y. et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell 36, 194–209.e9 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Guo, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell Proteom. 13, 372–387 (2014).

    CAS  Google Scholar 

  16. Musiani, D. et al. Proteomics profiling of arginine methylation defines PRMT5 substrate specificity. Sci. Signal. 12, eaat8388 (2019).

    CAS  PubMed  Google Scholar 

  17. Bedford, M. T. & Richard, S. Arginine methylation an emerging regulator of protein function. Mol. Cell 18, 263–272 (2005).

    CAS  PubMed  Google Scholar 

  18. Blanc, R. S. & Richard, S. Arginine methylation: the coming of age. Mol. Cell 65, 8–24 (2017).

    CAS  PubMed  Google Scholar 

  19. Lorton, B. M. & Shechter, D. Cellular consequences of arginine methylation. Cell Mol. Life Sci. 76, 2933–2956 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Brown, J. I., Koopmans, T., van Strien, J., Martin, N. I. & Frankel, A. Kinetic analysis of PRMT1 reveals multifactorial processivity and a sequential ordered mechanism. ChemBioChem 19, 85–99 (2018).

    CAS  PubMed  Google Scholar 

  21. Wang, M., Fuhrmann, J. & Thompson, P. R. Protein arginine methyltransferase 5 catalyzes substrate dimethylation in a distributive fashion. Biochemistry 53, 7884–7892 (2014).

    CAS  PubMed  Google Scholar 

  22. Dhar, S. et al. Loss of the major type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs. Sci. Rep. 3, 1311 (2013).

    PubMed  PubMed Central  Google Scholar 

  23. Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).

    CAS  PubMed  Google Scholar 

  24. Kruger, D. M., Neubacher, S. & Grossmann, T. N. Protein–RNA interactions: structural characteristics and hotspot amino acids. RNA 24, 1457–1465 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Meister, G. & Fischer, U. Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs. EMBO J. 21, 5853–5863 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Radzisheuskaya, A. et al. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat. Struct. Mol. Biol. 26, 999–1012 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bezzi, M. et al. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 27, 1903–1916 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Braun, C. J. et al. Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma. Cancer Cell 32, 411–426.e11 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wong, J. J., Au, A. Y., Ritchie, W. & Rasko, J. E. Intron retention in mRNA: no longer nonsense: known and putative roles of intron retention in normal and disease biology. Bioessays 38, 41–49 (2016).

    PubMed  Google Scholar 

  30. Agolini, E. et al. Expanding the clinical and molecular spectrum of PRMT7 mutations: 3 additional patients and review. Clin. Genet. 93, 675–681 (2018).

    CAS  PubMed  Google Scholar 

  31. Shah, M. A., Denton, E. L., Arrowsmith, C. H., Lupien, M. & Schapira, M. A global assessment of cancer genomic alterations in epigenetic mechanisms. Epigenetics Chromatin 7, 29 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Jarrold, J. & Davies, C. C. PRMTs and arginine methylation: cancer’s best-kept secret? Trends Mol. Med. 25, 993–1009 (2019).

    CAS  PubMed  Google Scholar 

  33. Hashimoto, M. et al. Severe hypomyelination and developmental defects are caused in mice lacking protein arginine methyltransferase 1 (PRMT1) in the central nervous system. J. Biol. Chem. 291, 2237–2245 (2016).

    CAS  PubMed  Google Scholar 

  34. Huang, J., Vogel, G., Yu, Z., Almazan, G. & Richard, S. Type II arginine methyltransferase PRMT5 regulates gene expression of inhibitors of differentiation/DNA binding Id2 and Id4 during glial cell differentiation. J. Biol. Chem. 286, 44424–44432 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim, J. D. et al. PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination. Sci. Adv. 1, e1500615 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. Simandi, Z. et al. PRMT1 and PRMT8 regulate retinoic acid-dependent neuronal differentiation with implications to neuropathology. Stem Cell 33, 726–741 (2015).

    CAS  Google Scholar 

  37. Calabretta, S. et al. Loss of PRMT5 promotes PDGFRα degradation during oligodendrocyte differentiation and myelination. Dev. Cell 46, 426–440.e5 (2018).

    CAS  PubMed  Google Scholar 

  38. Karkhanis, V., Hu, Y. J., Baiocchi, R. A., Imbalzano, A. N. & Sif, S. Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem. Sci. 36, 633–641 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Carilla-Latorre, S. et al. MidA is a putative methyltransferase that is required for mitochondrial complex I function. J. Cell Sci. 123, 1674–1683 (2010).

    CAS  PubMed  Google Scholar 

  40. Zurita Rendon, O., Silva Neiva, L., Sasarman, F. & Shoubridge, E. A. The arginine methyltransferase NDUFAF7 is essential for complex I assembly and early vertebrate embryogenesis. Hum. Mol. Genet. 23, 5159–5170 (2014).

    PubMed  PubMed Central  Google Scholar 

  41. Choi, J. H. et al. PRMT1 mediates RANKL-induced osteoclastogenesis and contributes to bone loss in ovariectomized mice. Exp. Mol. Med. 50, 111 (2018).

    PubMed Central  Google Scholar 

  42. Kota, S. K., Roening, C., Patel, N., Kota, S. B. & Baron, R. PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression. Bone 117, 37–46 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ramachandran, J., Liu, Z., Gray, R. S. & Vokes, S. A. PRMT5 is necessary to form distinct cartilage identities in the knee and long bone. Dev. Biol. 456, 154–163 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Min, Z. et al. Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648. Cell Death Dis. 10, 581 (2019).

    PubMed  PubMed Central  Google Scholar 

  45. Dong, Y. et al. Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2. Cell Signal. 34, 55–65 (2017).

    CAS  PubMed  Google Scholar 

  46. Beltran-Alvarez, P. et al. Protein arginine methyl transferases-3 and -5 increase cell surface expression of cardiac sodium channel. FEBS Lett. 587, 3159–3165 (2013).

    CAS  PubMed  Google Scholar 

  47. Chen, M., Yi, B. & Sun, J. Inhibition of cardiomyocyte hypertrophy by protein arginine methyltransferase 5. J. Biol. Chem. 289, 24325–24335 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Murata, K. et al. PRMT1 deficiency in mouse juvenile heart induces dilated cardiomyopathy and reveals cryptic alternative splicing products. iScience 8, 200–213 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Onwuli, D. O., Rigau-Roca, L., Cawthorne, C. & Beltran-Alvarez, P. Mapping arginine methylation in the human body and cardiac disease. Proteomics Clin. Appl. 11, 1600106 (2017).

    Google Scholar 

  50. Pyun, J. H. et al. Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nat. Commun. 9, 5107 (2018).

    PubMed  PubMed Central  Google Scholar 

  51. Wang, Y., Ju, C., Hu, J., Huang, K. & Yang, L. PRMT4 overexpression aggravates cardiac remodeling following myocardial infarction by promoting cardiomyocyte apoptosis. Biochem. Biophys. Res. Commun. 520, 645–650 (2019).

    CAS  PubMed  Google Scholar 

  52. Migliori, V. et al. Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nat. Struct. Mol. Biol. 19, 136–144 (2012).

    CAS  PubMed  Google Scholar 

  53. Yuan, C. C. et al. Histone H3R2 symmetric dimethylation and histone H3K4 trimethylation are tightly correlated in eukaryotic genomes. Cell Rep. 1, 83–90 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hyllus, D. et al. PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation. Genes Dev. 21, 3369–3380 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen, H., Lorton, B., Gupta, V. & Shechter, D. A TGFβ–PRMT5–MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression. Oncogene 36, 373–386 (2017).

    CAS  PubMed  Google Scholar 

  56. Cheung, N., Chan, L. C., Thompson, A., Cleary, M. L. & So, C. W. Protein arginine-methyltransferase-dependent oncogenesis. Nat. Cell Biol. 9, 1208–1215 (2007).

    CAS  PubMed  Google Scholar 

  57. Greenblatt, S. M. et al. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis. Cancer Cell 33, 1111–1127.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gao, Y. et al. The dual function of PRMT1 in modulating epithelial–mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1. Sci. Rep. 6, 19874 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chiang, K. et al. PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression. Cell Rep. 21, 3498–3513 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hu, D. et al. Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis. Nat. Commun. 6, 8419 (2015).

    CAS  PubMed  Google Scholar 

  61. Hsu, T. Y. et al. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525, 384–388 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Koh, C. M. et al. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523, 96–100 (2015).

    CAS  PubMed  Google Scholar 

  63. Wang, L., Pal, S. & Sif, S. Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol. Cell. Biol. 28, 6262–6277 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gao, G., Dhar, S. & Bedford, M. T. PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1. Nucleic Acids Res. 45, 4359–4369 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Anczukow, O. & Krainer, A. R. Splicing-factor alterations in cancers. RNA 22, 1285–1301 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Dvinge, H., Kim, E., Abdel-Wahab, O. & Bradley, R. K. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. 16, 413–430 (2016).

    CAS  Google Scholar 

  67. Zhang, L. et al. Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. eLife 4, e07938 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Greenblatt, S. M., Liu, F. & Nimer, S. D. Arginine methyltransferases in normal and malignant hematopoiesis. Exp. Hematol. 44, 435–441 (2016).

    CAS  PubMed  Google Scholar 

  69. Gerhart, S. V. et al. Activation of the p53–MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci. Rep. 8, 9711 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Sachamitr, P. et al. Disruption of splicing, proliferation and stemness via PRMT5 inhibition as a therapeutic strategy for GBM. Nat. Commun. 12, 979 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Bedford, M. T. & Clarke, S. G. Protein arginine methylation in mammals: who, what, and why. Mol. Cell 33, 1–13 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Choucair, A. et al. The arginine methyltransferase PRMT1 regulates IGF-1 signaling in breast cancer. Oncogene 38, 4015–4027 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Le Romancer, M. et al. Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol. Cell 31, 212–221 (2008).

    PubMed  Google Scholar 

  74. Deng, X. et al. Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth. Oncogene 36, 1223–1231 (2017).

    CAS  PubMed  Google Scholar 

  75. Gu, H. et al. Quantitative profiling of post-translational modifications by immunoaffinity enrichment and LC-MS/MS in cancer serum without immunodepletion. Mol. Cell Proteom. 15, 692–702 (2016).

    CAS  Google Scholar 

  76. Wang, Y. P. et al. Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Mol. Cell 64, 673–687 (2016).

    CAS  Google Scholar 

  77. Zhong, X. Y. et al. CARM1 methylates GAPDH to regulate glucose metabolism and is suppressed in liver cancer. Cell Rep. 24, 3207–3223 (2018).

    CAS  PubMed  Google Scholar 

  78. Yamamoto, T. et al. Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Nat. Commun. 5, 3480 (2014).

    PubMed  Google Scholar 

  79. Backe, S. J., Sager, R. A., Woodford, M. R., Makedon, A. M. & Mollapour, M. Post-translational modifications of Hsp90 and translating the chaperone code. J. Biol. Chem. 295, 11099–11117 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Nitika Porter, C. M., Truman, A. W. & Truttmann, M. C. Post-translational modifications of Hsp70 family proteins: expanding the chaperone code. J. Biol. Chem. 295, 10689–10708 (2020).

    PubMed  Google Scholar 

  81. Gao, W. W. et al. Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation. Proc. Natl Acad. Sci. USA 112, E3327–3336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Szewczyk, M. M. et al. Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response. Nat. Commun. 11, 2396 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, L. et al. Methylation of HSP70 orchestrates its binding to and stabilization of BCL2 mRNA and renders pancreatic cancer cells resistant to therapeutics. Cancer Res. 80, 4500–4513 (2020).

    CAS  PubMed  Google Scholar 

  84. Deng, G. et al. Foxp3 post-translational modifications and Treg suppressive activity. Front. Immunol. 10, 2486 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kagoya, Y. et al. Arginine methylation of FOXP3 is crucial for the suppressive function of regulatory T cells. J. Autoimmun. 97, 10–21 (2019).

    CAS  PubMed  Google Scholar 

  86. Nagai, Y. et al. PRMT5 associates with the FOXP3 homomer and when disabled enhances targeted p185(erbB2/neu) tumor immunotherapy. Front. Immunol. 10, 174 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Geoghegan, V., Guo, A., Trudgian, D., Thomas, B. & Acuto, O. Comprehensive identification of arginine methylation in primary T cells reveals regulatory roles in cell signalling. Nat. Commun. 6, 6758 (2015).

    CAS  PubMed  Google Scholar 

  88. Metz, P. J. et al. Symmetric arginine dimethylation is selectively required for mRNA splicing and the initiation of type I and type III interferon signaling. Cell Rep. 30, 1935–1950.e8 (2020).

    CAS  PubMed  Google Scholar 

  89. Benci, J. L. et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell 178, 933–948.e14 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Scaramuzzino, C. et al. Protein arginine methyltransferase 1 and 8 interact with FUS to modify its sub-cellular distribution and toxicity in vitro and in vivo. PLoS ONE 8, e61576 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hofweber, M. et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173, 706–719.e13 (2018).

    CAS  PubMed  Google Scholar 

  92. Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation–π interactions. Cell 173, 720–734.e15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ryan, V. H. et al. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell 69, 465–479.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chang, B., Chen, Y., Zhao, Y. & Bruick, R. K. JMJD6 is a histone arginine demethylase. Science 318, 444–447 (2007).

    CAS  PubMed  Google Scholar 

  96. Walport, L. J. et al. Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases. Nat. Commun. 7, 11974 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Islam, M. S. et al. Biochemical and structural investigations clarify the substrate selectivity of the 2-oxoglutarate oxygenase JMJD6. J. Biol. Chem. 294, 11637–11652 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Tsai, W. C. et al. Arginine demethylation of G3BP1 promotes stress granule assembly. J. Biol. Chem. 291, 22671–22685 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Tsai, W. C., Reineke, L. C., Jain, A., Jung, S. Y. & Lloyd, R. E. Histone arginine demethylase JMJD6 is linked to stress granule assembly through demethylation of the stress granule-nucleating protein G3BP1. J. Biol. Chem. 292, 18886–18896 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ganesan, A., Arimondo, P. B., Rots, M. G., Jeronimo, C. & Berdasco, M. The timeline of epigenetic drug discovery: from reality to dreams. Clin. Epigenetics 11, 174 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ratovitski, T., Arbez, N., Stewart, J. C., Chighladze, E. & Ross, C. A. PRMT5-mediated symmetric arginine dimethylation is attenuated by mutant huntingtin and is impaired in Huntington’s disease (HD). Cell Cycle 14, 1716–1729 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Maiuri, T. et al. DNA damage repair in Huntington’s disease and other neurodegenerative diseases. Neurotherapeutics 16, 948–956 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Suganuma, T. et al. MPTAC determines APP fragmentation via sensing sulfur amino acid catabolism. Cell Rep. 24, 1585–1596 (2018).

    CAS  PubMed  Google Scholar 

  104. Quan, X. et al. The protein arginine methyltransferase PRMT5 regulates Aβ-induced toxicity in human cells and Caenorhabditis elegans models of Alzheimer’s disease. J. Neurochem. 134, 969–977 (2015).

    CAS  PubMed  Google Scholar 

  105. Boulanger, M. C. et al. Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression. J. Virol. 79, 124–131 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Kzhyshkowska, J. et al. Heterogeneous nuclear ribonucleoprotein E1B-AP5 is methylated in its Arg-Gly-Gly (RGG) box and interacts with human arginine methyltransferase HRMT1L1. Biochem. J. 358, 305–314 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rho, J., Choi, S., Seong, Y. R., Choi, J. & Im, D. S. The arginine-1493 residue in QRRGRTGR1493G motif IV of the hepatitis C virus NS3 helicase domain is essential for NS3 protein methylation by the protein arginine methyltransferase 1. J. Virol. 75, 8031–8044 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Shire, K. et al. Regulation of the EBNA1 Epstein–Barr virus protein by serine phosphorylation and arginine methylation. J. Virol. 80, 5261–5272 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Souki, S. K., Gershon, P. D. & Sandri-Goldin, R. M. Arginine methylation of the ICP27 RGG box regulates ICP27 export and is required for efficient herpes simplex virus 1 replication. J. Virol. 83, 5309–5320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Friedrich, S. et al. Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45. RNA 22, 1574–1591 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Iacovides, D. C., O’Shea, C. C., Oses-Prieto, J., Burlingame, A. & McCormick, F. Critical role for arginine methylation in adenovirus-infected cells. J. Virol. 81, 13209–13217 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Li, Y. J., Stallcup, M. R. & Lai, M. M. Hepatitis delta virus antigen is methylated at arginine residues, and methylation regulates subcellular localization and RNA replication. J. Virol. 78, 13325–13334 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Lubyova, B. et al. PRMT5: a novel regulator of hepatitis B virus replication and an arginine methylase of HBV core. PLoS ONE 12, e0186982 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. Murakami, H. et al. Protein arginine N-methyltransferases 5 and 7 promote HIV-1 production. Viruses 12, 355 (2020).

    CAS  PubMed Central  Google Scholar 

  115. Singhroy, D. N. et al. Automethylation of protein arginine methyltransferase 6 (PRMT6) regulates its stability and its anti-HIV-1 activity. Retrovirology 10, 73 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Xie, B., Invernizzi, C. F., Richard, S. & Wainberg, M. A. Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat interactions with both cyclin T1 and the Tat transactivation region. J. Virol. 81, 4226–4234 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Fulcher, A. J. et al. The protein arginine methyltransferase PRMT6 inhibits HIV-1 Tat nucleolar retention. Biochim. Biophys. Acta 1863, 254–262 (2016).

    CAS  PubMed  Google Scholar 

  118. Sivakumaran, H. et al. Arginine methylation increases the stability of human immunodeficiency virus type 1 Tat. J. Virol. 83, 11694–11703 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kaufmann, S. H. E., Dorhoi, A., Hotchkiss, R. S. & Bartenschlager, R. Host-directed therapies for bacterial and viral infections. Nat. Rev. Drug Discov. 17, 35–56 (2018).

    CAS  PubMed  Google Scholar 

  120. Sun, Q. et al. TGF-β upregulated mitochondria mass through the SMAD2/3→C/EBPβ→PRMT1 signal pathway in primary human lung fibroblasts. J. Immunol. 202, 37–47 (2019).

    CAS  PubMed  Google Scholar 

  121. Sun, Q. et al. Upregulated protein arginine methyltransferase 1 by IL-4 increases eotaxin-1 expression in airway epithelial cells and participates in antigen-induced pulmonary inflammation in rats. J. Immunol. 188, 3506–3512 (2012).

    CAS  PubMed  Google Scholar 

  122. Zakrzewicz, D. et al. Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis. Biochim. Biophys. Acta 1852, 2678–2688 (2015).

    CAS  PubMed  Google Scholar 

  123. Kim, J. H. et al. The role of protein arginine methyltransferases in inflammatory responses. Mediators Inflamm. 2016, 4028353 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. Harris, D. P., Bandyopadhyay, S., Maxwell, T. J., Willard, B. & DiCorleto, P. E. Tumor necrosis factor (TNF)-α induction of CXCL10 in endothelial cells requires protein arginine methyltransferase 5 (PRMT5)-mediated nuclear factor (NF)-κB p65 methylation. J. Biol. Chem. 289, 15328–15339 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Harris, D. P., Chandrasekharan, U. M., Bandyopadhyay, S., Willard, B. & DiCorleto, P. E. PRMT5-mediated methylation of NF-κB p65 at Arg174 is required for endothelial CXCL11 gene induction in response to TNF-α and IFN-γ costimulation. PLoS ONE 11, e0148905 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. Covic, M. et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-κB-dependent gene expression. EMBO J. 24, 85–96 (2005).

    CAS  PubMed  Google Scholar 

  127. Harrison, M. J., Tang, Y. H. & Dowhan, D. H. Protein arginine methyltransferase 6 regulates multiple aspects of gene expression. Nucleic Acids Res. 38, 2201–2216 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hassa, P. O., Covic, M., Bedford, M. T. & Hottiger, M. O. Protein arginine methyltransferase 1 coactivates NF-κB-dependent gene expression synergistically with CARM1 and PARP1. J. Mol. Biol. 377, 668–678 (2008).

    CAS  PubMed  Google Scholar 

  129. Couto, E. S. A. et al. Protein arginine methyltransferases in cardiovascular and neuronal function. Mol. Neurobiol. 57, 1716–1732 (2020).

    Google Scholar 

  130. Zakrzewicz, D., Zakrzewicz, A., Preissner, K. T., Markart, P. & Wygrecka, M. Protein arginine methyltransferases (PRMTs): promising targets for the treatment of pulmonary disorders. Int. J. Mol. Sci. 13, 12383–12400 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Arrowsmith, C. H. et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536–541 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Blagg, J. & Workman, P. Choose and use your chemical probe wisely to explore cancer biology. Cancer Cell 32, 9–25 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Frye, S. V. The art of the chemical probe. Nat. Chem. Biol. 6, 159–161 (2010).

    CAS  PubMed  Google Scholar 

  134. Dilworth, D. & Barsyte-Lovejoy, D. Targeting protein methylation: from chemical tools to precision medicines. Cell Mol. Life Sci. 76, 2967–2985 (2019).

    CAS  PubMed  Google Scholar 

  135. Li, A. S. M. et al. Chemical probes for protein arginine methyltransferases. Methods 175, 30–43 (2020).

    CAS  PubMed  Google Scholar 

  136. Schapira, M. & Ferreira de Freitas, R. Structural biology and chemistry of protein arginine methyltransferases. Medchemcomm 5, 1779–1788 (2014).

    CAS  PubMed  Google Scholar 

  137. Antonysamy, S. et al. Crystal structure of the human PRMT5:MEP50 complex. Proc. Natl Acad. Sci. USA 109, 17960–17965 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Boriack-Sjodin, P. A. et al. Structural insights into ternary complex formation of human CARM1 with various substrates. ACS Chem. Biol. 11, 763–771 (2016).

    CAS  PubMed  Google Scholar 

  139. Fedoriw, A. et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell 36, 100–114.e25 (2019).

    CAS  PubMed  Google Scholar 

  140. Chan-Penebre, E. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432–437 (2015).

    CAS  PubMed  Google Scholar 

  141. Ferreira de Freitas, R., Ivanochko, D. & Schapira, M. Methyltransferase inhibitors: competing with, or exploiting the bound cofactor. Molecules 24, 4492 (2019).

    CAS  PubMed Central  Google Scholar 

  142. Campagna-Slater, V. et al. Structural chemistry of the histone methyltransferases cofactor binding site. J. Chem. Inf. Model. 51, 612–623 (2011).

    CAS  PubMed  Google Scholar 

  143. Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

    CAS  PubMed  Google Scholar 

  144. Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).

    CAS  PubMed  Google Scholar 

  146. Bonday, Z. Q. et al. LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity. ACS Med. Chem. Lett. 9, 612–617 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Cai, X. C. et al. A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion. eLife 8, e47110 (2019).

    PubMed  PubMed Central  Google Scholar 

  148. Pande, V. et al. A chemical probe for the methyl transferase PRMT5 with a novel binding mode. ACS Med. Chem. Lett. 11, 2227–2231 (2020).

    CAS  PubMed  Google Scholar 

  149. Lin, H. et al. Discovery of potent and selective covalent protein arginine methyltransferase 5 (PRMT5) inhibitors. ACS Med. Chem. Lett. 10, 1033–1038 (2019).

    PubMed  PubMed Central  Google Scholar 

  150. Shen, Y. et al. Discovery of a first-in-class protein arginine methyltransferase 6 (PRMT6) covalent inhibitor. J. Med. Chem. 63, 5477–5487 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Mitchell, L. H. et al. Aryl pyrazoles as potent inhibitors of arginine methyltransferases: identification of the first PRMT6 tool compound. ACS Med. Chem. Lett. 6, 655–659 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Shen, Y. et al. Discovery of a potent, selective, and cell-active dual inhibitor of protein arginine methyltransferase 4 and protein arginine methyltransferase 6. J. Med. Chem. 59, 9124–9139 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Palte, R. L. et al. Allosteric modulation of protein arginine methyltransferase 5 (PRMT5). ACS Med. Chem. Lett. 11, 1688–1693 (2020).

    CAS  PubMed  Google Scholar 

  154. Shen, Y. et al. A first-in-class, highly selective and cell-active allosteric inhibitor of protein arginine methyltransferase 6 (PRMT6). https://doi.org/10.1101/2020.12.04.412569v1 (2020).

  155. Kaniskan, H. U. et al. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew. Chem. 54, 5166–5170 (2015).

    CAS  Google Scholar 

  156. Siu, L. L. et al. METEOR-1: a phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours. Ann. Oncol. 30, mdz244 (2019).

    Google Scholar 

  157. Kalev, P. et al. MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage. Cancer Cell 39, 209–224 (2021).

    CAS  PubMed  Google Scholar 

  158. Alinari, L. et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125, 2530–2543 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Mounir, Z. et al. ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the androgen receptor. eLife 5, e13964 (2016).

    PubMed  PubMed Central  Google Scholar 

  161. Zhao, Q. et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat. Struct. Mol. Biol. 16, 304–311 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Secker, K. A. et al. Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9. Oncogene 38, 7181–7195 (2019).

    CAS  PubMed  Google Scholar 

  163. Gao, G. et al. PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic Acids Res. 47, 5038–5048 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Raposo, A. E. & Piller, S. C. Protein arginine methylation: an emerging regulator of the cell cycle. Cell Div. 13, 3 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. Clarke, T. L. et al. PRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination. Mol. Cell 65, 900–916.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Hamard, P. J. et al. PRMT5 regulates DNA repair by controlling the alternative splicing of histone-modifying enzymes. Cell Rep. 24, 2643–2657 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Musiani, D. et al. PRMT1 is recruited via DNA-PK to chromatin where it sustains the senescence-associated secretory phenotype in response to cisplatin. Cell Rep. 30, 1208–1222.e9 (2020).

    CAS  PubMed  Google Scholar 

  168. Bajbouj, K. et al. Abstract 4711: PRMT5 selective inhibitor enhances therapeutic efficacy of cisplatin in lung adenocarcinoma cells. Cancer Res. 79, 4711–4711 (2019).

    Google Scholar 

  169. Hsu, M. C. et al. Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression. Cancers 11, 8 (2018).

    PubMed Central  Google Scholar 

  170. Yang, Y. et al. Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. Mol. Cell 53, 484–497 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lytle, N. K., Barber, A. G. & Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. 18, 669–680 (2018).

    CAS  Google Scholar 

  172. Jin, Y. et al. Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. J. Clin. Invest. 126, 3961–3980 (2016).

    PubMed  PubMed Central  Google Scholar 

  173. Zhou, Z. et al. A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy. EBioMedicine 44, 98–111 (2019).

    PubMed  PubMed Central  Google Scholar 

  174. AbuHammad, S. et al. Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proc. Natl Acad. Sci. USA 116, 17990–18000 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Holmes, B. et al. The protein arginine methyltransferase PRMT5 confers therapeutic resistance to mTOR inhibition in glioblastoma. J. Neurooncol. 145, 11–22 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Zhu, F. et al. PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells. Leukemia 33, 2898–2911 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Snyder, K. et al. PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease. JCI Insight https://doi.org/10.1172/jci.insight.131099 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Sun, Q. et al. PRMT1 upregulated by epithelial proinflammatory cytokines participates in COX2 expression in fibroblasts and chronic antigen-induced pulmonary inflammation. J. Immunol. 195, 298–306 (2015).

    CAS  PubMed  Google Scholar 

  179. Zheng, Y. et al. Protein arginine methyltransferase 5 inhibition upregulates Foxp3+ regulatory T cells frequency and function during the ulcerative colitis. Front. Immunol. 8, 596 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. Hartley, A. V. & Lu, T. Modulating the modulators: regulation of protein arginine methyltransferases by post-translational modifications. Drug Discov. Today 25, 1735–1743 (2020).

    CAS  PubMed  Google Scholar 

  181. Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Shen, Y. et al. Discovery of first-in-class protein arginine methyltransferase 5 (PRMT5) degraders. J. Med. Chem. 63, 9977–9989 (2020).

    CAS  PubMed  Google Scholar 

  183. Bowling, E. A. et al. Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer. Cell 184, 384–403.e21 (2021).

    CAS  PubMed  Google Scholar 

  184. Fu, T., Lv, X., Kong, Q. & Yuan, C. A novel SHARPIN–PRMT5–H3R2me1 axis is essential for lung cancer cell invasion. Oncotarget 8, 54809–54820 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. Jing, P. et al. Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling. Cancer Lett. 427, 38–48 (2018).

    CAS  PubMed  Google Scholar 

  186. Cheng, D. et al. PRMT7 contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with HSPA5 and EEF2. Onco Targets Ther. 11, 4869–4876 (2018).

    PubMed  PubMed Central  Google Scholar 

  187. Park, M. J. et al. Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo. J. Hepatol. 61, 1151–1157 (2014).

    CAS  PubMed  Google Scholar 

  188. Nahon, J. E., Groeneveldt, C., Geerling, J. J., van Eck, M. & Hoekstra, M. Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor-driven transcription of hepatic lipogenic genes in vivo. Br. J. Pharmacol. 175, 3175–3183 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Huang, L. et al. Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis. J. Biol. Chem. 293, 10884–10894 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Benhenda, S. et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J. Virol. 87, 4360–4371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Liu, L. et al. Arginine methylation of SREBP1a via PRMT5 promotes de novo lipogenesis and tumor growth. Cancer Res. 76, 1260–1272 (2016).

    CAS  PubMed  Google Scholar 

  192. Jiang, H. et al. PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. Cancer Med. 7, 869–882 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Li, Z. et al. The LINC01138 drives malignancies via activating arginine methyltransferase 5 in hepatocellular carcinoma. Nat. Commun. 9, 1572 (2018).

    PubMed  PubMed Central  Google Scholar 

  194. Zhu, K. et al. Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT-β-catenin signaling pathway. Carcinogenesis 41, 130–138 (2020).

    CAS  PubMed  Google Scholar 

  195. Chan, L. H. et al. PRMT6 regulates RAS/RAF binding and MEK/ERK-mediated cancer stemness activities in hepatocellular carcinoma through CRAF methylation. Cell Rep. 25, 690–701.e8 (2018).

    CAS  PubMed  Google Scholar 

  196. Wang, Y. et al. Oncogenic functions of Gli1 in pancreatic adenocarcinoma are supported by its PRMT1-mediated methylation. Cancer Res. 76, 7049–7058 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Qin, Y. et al. PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis. Cell Commun. Signal. 17, 30 (2019).

    PubMed  PubMed Central  Google Scholar 

  198. Choi, S. et al. Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6–FOXO3 axis. Autophagy 15, 1069–1081 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Blanc, R. S. et al. Arginine methylation by PRMT1 regulates muscle stem cell fate. Mol. Cell. Biol. 37, e00457-16 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. Sanchez, G. et al. A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy. Nucleic Acids Res. 44, 2661–2676 (2016).

    PubMed  Google Scholar 

  201. Cheng, D., Cote, J., Shaaban, S. & Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 25, 71–83 (2007).

    PubMed  Google Scholar 

  202. Hsu, J. H. et al. PRMT1-mediated translation regulation is a crucial vulnerability of cancer. Cancer Res. 77, 4613–4625 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhang, B. et al. Arginine methyltransferase inhibitor-1 inhibits sarcoma viability in vitro and in vivo. Oncol. Lett. 16, 2161–2166 (2018).

    PubMed  PubMed Central  Google Scholar 

  204. Michaud-Levesque, J. & Richard, S. Thrombospondin-1 is a transcriptional repression target of PRMT6. J. Biol. Chem. 284, 21338–21346 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Akter, K. A. et al. FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation. Tumour Biol. 37, 4531–4539 (2016).

    CAS  PubMed  Google Scholar 

  206. Karakashev, S. et al. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat. Commun. 9, 631 (2018).

    PubMed  PubMed Central  Google Scholar 

  207. Bao, X. et al. Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer. J. Histochem. Cytochem. 61, 206–217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Krishna, M. B. et al. Impaired arginine metabolism coupled to a defective redox conduit contributes to low plasma nitric oxide in polycystic ovary syndrome. Cell Physiol. Biochem. 43, 1880–1892 (2017).

    CAS  PubMed  Google Scholar 

  209. Tradewell, M. L. et al. Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum. Mol. Genet. 21, 136–149 (2012).

    PubMed  Google Scholar 

  210. Chitiprolu, M. et al. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nat. Commun. 9, 2794 (2018).

    PubMed  PubMed Central  Google Scholar 

  211. Penney, J. et al. Loss of protein arginine methyltransferase 8 alters synapse composition and function, resulting in behavioral defects. J. Neurosci. 37, 8655–8666 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Kim, H. J. et al. Protein arginine methylation facilitates KCNQ channel–PIP2 interaction leading to seizure suppression. eLife 5, e17159 (2016).

    PubMed  PubMed Central  Google Scholar 

  213. Lee, S. Y. et al. Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells. Exp. Mol. Med. 51, 1–14 (2019).

    PubMed  PubMed Central  Google Scholar 

  214. Banasavadi-Siddegowda, Y. K. et al. PRMT5–PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells. Oncogene 36, 263–274 (2017).

    CAS  PubMed  Google Scholar 

  215. Du, C. et al. A PRMT5–RNF168–SMURF2 axis controls H2AX proteostasis. Cell Rep. 28, 3199–3211.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Yan, F. et al. Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma. Cancer Res. 74, 1752–1765 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Liu, X., Xu, X., Shang, R. & Chen, Y. Asymmetric dimethylarginine (ADMA) as an important risk factor for the increased cardiovascular diseases and heart failure in chronic kidney disease. Nitric Oxide 78, 113–120 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Matsuguma, K. et al. Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease. J. Am. Soc. Nephrol. 17, 2176–2183 (2006).

    CAS  PubMed  Google Scholar 

  219. Wu, M. et al. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys. FASEB J. 33, 6948–6956 (2019).

    CAS  PubMed  Google Scholar 

  220. Kim, D. et al. Ubiquitination-dependent CARM1 degradation facilitates Notch1-mediated podocyte apoptosis in diabetic nephropathy. Cell Signal. 26, 1774–1782 (2014).

    CAS  PubMed  Google Scholar 

  221. Cho, J. H. et al. Arginine methylation-dependent regulation of ASK1 signaling by PRMT1. Cell Death Differ. 19, 859–870 (2012).

    CAS  PubMed  Google Scholar 

  222. Guendel, I. et al. Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function. PLoS ONE 5, e11379 (2010).

    PubMed  PubMed Central  Google Scholar 

  223. Liu, L. M. et al. Methylation of C/EBPα by PRMT1 inhibits its tumor-suppressive function in breast cancer. Cancer Res. 79, 2865–2877 (2019).

    CAS  PubMed  Google Scholar 

  224. Nakai, K. et al. The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells. Breast Cancer 25, 74–80 (2018).

    PubMed  Google Scholar 

  225. Qi, C. et al. Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor α. J. Biol. Chem. 277, 28624–28630 (2002).

    CAS  PubMed  Google Scholar 

  226. Zhong, J. et al. Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma. FEBS J. 279, 316–335 (2012).

    CAS  PubMed  Google Scholar 

  227. Wang, L. et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25, 21–36 (2014).

    PubMed  PubMed Central  Google Scholar 

  228. Liu, J. et al. Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer. EMBO Rep. 21, e48597 (2020).

    CAS  PubMed  Google Scholar 

  229. Wang, L. et al. MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs. Sci. Adv. 1, e1500463 (2015).

    PubMed  PubMed Central  Google Scholar 

  230. Hiken, J. F. et al. Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer. Oncogene 36, 2319–2327 (2017).

    CAS  PubMed  Google Scholar 

  231. Dowhan, D. H. et al. Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes. Endocr. Relat. Cancer 19, 509–526 (2012).

    CAS  PubMed  Google Scholar 

  232. Veland, N. et al. The arginine methyltransferase PRMT6 regulates DNA methylation and contributes to global DNA hypomethylation in cancer. Cell Rep. 21, 3390–3397 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Wang, Z. et al. PRMT5 determines the sensitivity to chemotherapeutics by governing stemness in breast cancer. Breast Cancer Res. Treat. 168, 531–542 (2018).

    CAS  PubMed  Google Scholar 

  234. Rengasamy, M. et al. The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer. Nucleic Acids Res. 45, 11106–11120 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Powers, M. A., Fay, M. M., Factor, R. E., Welm, A. L. & Ullman, K. S. Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res. 71, 5579–5587 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Yao, R. et al. PRMT7 induces epithelial-to-mesenchymal transition and promotes metastasis in breast cancer. Cancer Res. 74, 5656–5667 (2014).

    CAS  PubMed  Google Scholar 

  237. Liu, Y. et al. Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling. elife 9, e57617 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Geng, P. et al. Automethylation of protein arginine methyltransferase 7 and its impact on breast cancer progression. FASEB J. 31, 2287–2300 (2017).

    CAS  PubMed  Google Scholar 

  239. Eram, M. S. et al. A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases. ACS Chem. Biol. 11, 772–781 (2016).

    CAS  PubMed  Google Scholar 

  240. Hoekstra, M. et al. Inhibition of PRMT3 activity reduces hepatic steatosis without altering atherosclerosis susceptibility in apoE knockout mice. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 1402–1409 (2019).

    CAS  PubMed  Google Scholar 

  241. Drew, A. E. et al. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Sci. Rep. 7, 17993 (2017).

    PubMed  PubMed Central  Google Scholar 

  242. Nakayama, K. et al. TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. Oncotarget 9, 18480–18493 (2018).

    PubMed  PubMed Central  Google Scholar 

  243. He, Y. et al. Inhibition of protein arginine methyltransferase 6 reduces reactive oxygen species production and attenuates aminoglycoside- and cisplatin-induced hair cell death. Theranostics 10, 133–150 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Duncan, K. W. et al. Structure and property guided design in the identification of PRMT5 tool compound EPZ015666. ACS Med. Chem. Lett. 7, 162–166 (2016).

    CAS  PubMed  Google Scholar 

  245. Gulla, A. et al. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32, 996–1002 (2018).

    CAS  PubMed  Google Scholar 

  246. Serio, J. et al. The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia. Oncogene 37, 450–460 (2018).

    CAS  PubMed  Google Scholar 

  247. Kaushik, S. et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 32, 499–509 (2018).

    CAS  PubMed  Google Scholar 

  248. Hu, G., Wang, X., Han, Y. & Wang, P. Protein arginine methyltransferase 5 promotes bladder cancer growth through inhibiting NF-κB dependent apoptosis. EXCLI J. 17, 1157–1166 (2018).

    PubMed  PubMed Central  Google Scholar 

  249. Millar, H. G. et al. In vivo efficacy and pharmacodynamic modulation of JNJ-64619178, a selective PRMT5 inhibitor, in human lung and hematologic preclinical models [abstract]. Cancer Res. 79 (Suppl.), 950 (2019).

    Google Scholar 

  250. Vinet, M. et al. Protein arginine methyltransferase 5: a novel therapeutic target for triple-negative breast cancers. Cancer Med. 8, 2414–2428 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Pastore, F. et al. PRMT5 inhibition modulates E2F1 methylation and gene regulatory networks leading to therapeutic efficacy in JAK2VF mutant MPN. Blood 134 (Suppl. 1), 473 (2019).

    Google Scholar 

  252. Lu, X. et al. PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood 132, 2026–2039 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Iderzorig, T. et al. Comparison of EMT mediated tyrosine kinase inhibitor resistance in NSCLC. Biochem. Biophys. Res. Commun. 496, 770–777 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Struck, A. W., Thompson, M. L., Wong, L. S. & Micklefield, J. S-Adenosyl-methionine-dependent methyltransferases: highly versatile enzymes in biocatalysis, biosynthesis and other biotechnological applications. Chembiochem 13, 2642–2655 (2012).

    CAS  PubMed  Google Scholar 

  255. Kishi, T., Tanaka, Y. & Ueda, K. Evidence for hypomethylation in two children with acute lymphoblastic leukemia and leukoencephalopathy. Cancer 89, 925–931 (2000).

    CAS  PubMed  Google Scholar 

  256. Hsu, C. P., Hsu, P. F., Chung, M. Y., Lin, S. J. & Lu, T. M. Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control. Cardiovasc. Diabetol. 13, 156 (2014).

    PubMed  PubMed Central  Google Scholar 

  257. Lu, T. M., Chung, M. Y., Lin, M. W., Hsu, C. P. & Lin, S. J. Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography. Int. J. Cardiol. 153, 135–140 (2011).

    PubMed  Google Scholar 

  258. Mittermayer, F. et al. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 26, 2536–2540 (2006).

    CAS  PubMed  Google Scholar 

  259. Lim, S. & Park, S. Role of vascular smooth muscle cell in the inflammation of atherosclerosis. BMB Rep. 47, 1–7 (2014).

    PubMed  PubMed Central  Google Scholar 

  260. Di Franco, M., Lucchino, B., Conti, F., Valesini, G. & Spinelli, F. R. Asymmetric dimethyl arginine as a biomarker of atherosclerosis in rheumatoid arthritis. Mediators Inflamm. 2018, 3897295 (2018).

    PubMed  PubMed Central  Google Scholar 

  261. Selley, M. L. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer’s disease. Neurobiol. Aging 24, 903–907 (2003).

    CAS  PubMed  Google Scholar 

  262. Chandrasekharan, U. M. et al. Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis. Arthritis Res. Ther. 20, 123 (2018).

    PubMed  PubMed Central  Google Scholar 

  263. Lemos, H., Huang, L., Prendergast, G. C. & Mellor, A. L. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat. Rev. Cancer 19, 162–175 (2019).

    CAS  PubMed  Google Scholar 

  264. Bode-Boger, S. M. et al. Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J. Am. Soc. Nephrol. 17, 1128–1134 (2006).

    PubMed  Google Scholar 

  265. Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892–23899 (2004).

    CAS  PubMed  Google Scholar 

  266. Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank P. J. Brown for reading and feedback on the manuscript. They also thank the reviewers for critical reading and suggestions. Q.W. is recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research (no. 430943). The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute (OGI-196), EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant 875510), Janssen, Merck KGaA (also known as EMD in Canada and the USA), Merck & Co. (also known as MSD outside Canada and the USA), Pfizer, Takeda and Wellcome (106169/ZZ14/Z).

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Authors and Affiliations

  1. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China

    Qin Wu

  2. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

    Qin Wu, Matthieu Schapira, Cheryl H. Arrowsmith & Dalia Barsyte-Lovejoy

  3. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Qin Wu & Cheryl H. Arrowsmith

  4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Qin Wu & Cheryl H. Arrowsmith

  5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Matthieu Schapira & Dalia Barsyte-Lovejoy

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Glossary

π-Stacking

Non-covalent bonding between aromatic moieties that can align themselves in a parallel or orthogonal fashion.

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A reversible molecular interaction driving condensation of macromolecules into a dense phase resembling liquid droplets and existing within a dilute phase.

Ribonucleoprotein

(RNP). A protein complex with ribonucleic acids to influence processing, localization and stability of the complex.

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Distinct interferon cytokine and signalling pathways where by type I (IFNα, IFNβ and others) and type III (IFNλ) interferons are thought to confer potent and tonic front-line inflammatory responses.

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A conformational switch facilitated by proteins or RNA that leads to destabilization of stem–loop RNA structures in 3′ regions.

R-loops

Transcription-associated RNA–DNA hybrid structures resulting in the displacement of single-stranded DNA.

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Wu, Q., Schapira, M., Arrowsmith, C.H. et al. Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nat Rev Drug Discov 20, 509–530 (2021). https://doi.org/10.1038/s41573-021-00159-8

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