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

Abstract

Despite 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.

Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients

“…Arginine-moieties of numerous proteins in histones and other molecular structures are methylated by PRMT in many tissues and cells, notably in red blood cells (Bollenbach et al 2020a ; b ). The physiological importance of arginine-dimethylated proteins is currently of major scientific interest (Greer and Shi 2012 ; Blanc and Richard 2017 ; Peng and Wong 2017 ; Beltran-Alvarez et al 2011 , 2014 , 2015 ; Samuel et al 2021 ; Sirover 2021 ). Besides their protein-related functions, arginine-dimethylated proteins are precursors of MMA, ADMA and SDMA.…”

“…The biological significance of authentic asymmetrically protein-arginine dimethylated (aPADiMe) proteins and of symmetrically protein-arginine dimethylated (sPADiMe) proteins in histones and beyond is little investigated and understood. In general, protein-arginine dimethylation (PADiMe) is considered to alter the inherent biological activity of the native proteins (Blanc and Richard 2017 ; Peng and Wong 2017 ; Greer and Shi 2012 ; Beltran-Alvarez et al 2011 , 2014 , 2015 ; Samuel et al 2021 ; Sirover 2021 ). PTM may also be considered as a source of metabolites that are involved in various pathways.…”

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

“…Proteins that promote lysine acetylation and organelle biogenesis engage sorting nexins at endosomes in plants and mammals, suggesting longstanding interactions (Zhang et al, 2014). The enzymes controlling these PTMs are emerging as cancer targets, and with clinical trials of inhibitors underway, there is a need to clarify their mechanisms of action (Dang and Wei, 2021;Samuel et al, 2021). The data presented here indicate that negative regulation of endosome recruitment of SNX3 and its associated retromer assembly (Lucas et al, 2016;Leneva et al, 2021) would be blocked by methyl transferase inhibitors, while a broad range of membrane reader interactions could be affected by acetyltransferase and deacetylase inhibitors.…”

Love is in the hair: arginine methylation of human hair proteins as novel cardiovascular biomarkers

“…These metabolites exercise a range of functions when released into the circulation, notably related to nitric oxide synthase inhibition. As such, high levels of methylarginine metabolites, such as ADMA, in serum are associated with endothelial dysfunction, provide well-known prognostic markers for cardiovascular risk and mortality (Jarzebska et al 2019;Mangoni et al 2021;Tsikas 2020) and correlate with cardiorespiratory dysfunction (Böger et al 1997;Krempl et al 2005;Leong et al 2008;Meinitzer et al 2007;Surdacki et al 1999;Tajti et al 2018;Yoo and Lee 2001;Zinellu et al 2018).…”