The regulation, functions and clinical relevance of arginine methylation

Abstract

Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes, including transcription, RNA processing, signal transduction cascades, the DNA damage response and liquid–liquid phase separation. Recent studies have provided considerable advances in the development of experimental tools and the identification of clinically relevant PRMT inhibitors. In this review, we discuss the regulation of PRMTs, their various cellular roles and the clinical relevance of PRMT inhibitors for the therapy of neurodegenerative diseases and cancer.

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Fig. 1: Epigenetic regulation by arginine methylation.
Fig. 2: Arginine methylation regulates pre-mRNA splicing of genes important for cell proliferation, differentiation and survival.
Fig. 3: Roles of arginine methylation in the DNA damage response.
Fig. 4: Arginine methylation regulates signalling pathways.
Fig. 5: Regulation of membraneless organelles by arginine methylation.

Change history

  • 02 August 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

E.G. acknowledges funding support from the NRF2016-CRP001-103 CRP award and from the RNA Biology Center at the Cancer Science Institute (CSI) of Singapore, National University of Singapore, and funding by the Singapore Ministry of Education’s Tier 3 grants (grant number MOE2014-T3-1-006). S.R. acknowledges funding from the Canadian Institutes of Health Research (grant number FDN-154303).

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Both authors contributed equally to researching data for the article, the discussion of content, and writing and editing of the manuscript before submission.

Correspondence to Ernesto Guccione or Stéphane Richard.

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Nature Reviews Molecular Cell Biology thanks M. Bedford, C. Davies and S. Nimer for their contribution to the peer review of this work.

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Supplementary information

Glossary

π-stacking interactions

Interactions between rings of aromatic amino acids.

Aromatic cages

Refers to a protein structure that recognizes trimethyllysine (Me3+) ions.

Paraspeckle

Membraneless nuclear compartment of poorly understood functions, which contains ribonucleoprotein particles.

Small nuclear ribonucleoproteins

(snRNPs). Ribonucleoprotein complexes that function in pre-mRNA splicing; they are assembled in the cytoplasm and imported into the nucleus.

Homologous recombination

(HR). A DNA double-strand break repair process, in which homologous sequences (usually sister chromatids) are used as templates for high fidelity repair.

Stress granules

Protein and RNA cytoplasmic aggregations that appear in stress conditions and contain translationally repressed mRNAs.

Internal ribosome entry site

(IRES). Internal mRNA sites that mediate cap-independent translation initiation.

Non-homologous end joining

A DNA double-strand break repair process, in which the two break ends are re-joined without the use of a homologous template.

Poly(ADP-ribose) polymerase

A family of enzymes that catalyse the addition of polymers of ADP-ribose to proteins.

R-loops

RNA–DNA hybrids, in which a single-stranded RNA hybridizes to a template strand in a DNA duplex and displaces the non-template strand as a loop.

Liquid–liquid phase separation

A process in which different liquids undergo demixing (phase separation) from their cellular surrounding, for example, in the formation of membraneless bodies.

Non-competitive

Refers to inhibitors that are able to reduce enzymatic activity while binding to the targeted enzyme in the presence of S-adenosylmethionine (SAM-non-competitive) or the substrate (substrate-non-competitive).

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Guccione, E., Richard, S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol 20, 642–657 (2019). https://doi.org/10.1038/s41580-019-0155-x

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