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The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

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Abstract

Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymological studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

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Acknowledgments

N.S. and J.K. were supported by NIH/NIGMS [P20GM103395]. D.S. is funded by an NIH/NIGMS grant [R01GM108646] and by The American Cancer Society—Robbie Sue Mudd Kidney Cancer Research Scholar Grant [124891-RSG-13-396-01-DMC]. We are grateful to Emmanuel Burgos for structural and enzymatic insight and for rendering Fig. 6. The analysis shown in Fig. 7 is based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov and from KM-plotter: http://kmplot.com. We thank the specimen donors to these projects for their essential contributions. We thank the many investigators studying PRMT5 and we apologize to the authors whose work on PRMT5 was not included due to space limitations.

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Correspondence to Jocelyn E. Krebs or David Shechter.

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Stopa, N., Krebs, J.E. & Shechter, D. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell. Mol. Life Sci. 72, 2041–2059 (2015). https://doi.org/10.1007/s00018-015-1847-9

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  • DOI: https://doi.org/10.1007/s00018-015-1847-9

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