Nicholson TB, Chen T, Richard S.. The physiological and pathophysiological role of PRMT1-mediated protein arginine methylation. Pharmacol Res 60: 466-474

Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Pharmacological Research (Impact Factor: 4.41). 08/2009; 60(6):466-74. DOI: 10.1016/j.phrs.2009.07.006
Source: PubMed


Post-translational modifications are well-known effectors in DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine-methylated proteins implicated in a variety of cellular processes including signal transduction, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMT1, the major asymmetric arginine methyltransferase, in cellular processes and its link to human diseases.

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    • "It is also the most conserved PRMT with sequence similarity higher than 90% in vertebrates and higher than 70% between human and budding yeast [2]. It is involved in various cellular processes including signal transduction modulation and transcriptional regulation [5], [6]. For example, interaction of PRMT1 with the cytoplasmic domain of interferon (IFN) α receptor [7] indicate its role in INF signaling. "
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    ABSTRACT: Protein arginine methyltransferase (PRMT) 1 is the most conserved and widely distributed PRMT in eukaryotes. PRMT8 is a vertebrate-restricted paralogue of PRMT1 with an extra N-terminal sequence and brain-specific expression. We use zebrafish (Danio rerio) as a vertebrate model to study PRMT8 function and putative redundancy with PRMT1. The transcripts of zebrafish prmt8 were specifically expressed in adult zebrafish brain and ubiquitously expressed from zygotic to early segmentation stage before the neuronal development. Whole-mount in situ hybridization revealed ubiquitous prmt8 expression pattern during early embryonic stages, similar to that of prmt1. Knockdown of prmt8 with antisense morpholino oligonucleotide phenocopied prmt1-knockdown, with convergence/extension defects at gastrulation. Other abnormalities observed later include short body axis, curled tails, small and malformed brain and eyes. Catalytically inactive prmt8 failed to complement the morphants, indicating the importance of methyltransferase activity. Full-length prmt8 but not prmt1 cRNA can rescue the phenotypic changes. Nevertheless, cRNA encoding Prmt1 fused with the N-terminus of Prmt8 can rescue the prmt8 morphants. In contrast, N-terminus- deleted but not full-length prmt8 cRNA can rescue the prmt1 morphants as efficiently as prmt1 cRNA. Abnormal brain morphologies illustrated with brain markers and loss of fluorescent neurons in a transgenic fish upon prmt8 knockdown confirm the critical roles of prmt8 in neural development. In summery, our study is the first report showing the expression and function of prmt8 in early zebrafish embryogenesis. Our results indicate that prmt8 may play important roles non-overlapping with prmt1 in embryonic and neural development depending on its specific N-terminus.
    PLoS ONE 03/2013; 8(3):e55221. DOI:10.1371/journal.pone.0055221 · 3.23 Impact Factor
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    • "Arginine methylation is catalyzed by protein-arginine-N-methyltransferases (PRMTs) utilizing S-adenosyl-L-methionine (AdoMet) as the donor of methyl group. PRMT1, a member of 11 PRMTs family, is a type I methyltransferase that transfers a methyl group from AdoMet to guanidino nitrogens of arginine residues to form mono-methyl and asymmetric dimethyl arginine [20], [21]. PRMT1 is the major asymmetric arginine methyltransferase, contributing to as much as 85% of all cellular PRMT activity. "
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    ABSTRACT: Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is one of causative genes for familial amyotrophic lateral sclerosis (ALS). In order to identify binding partners for FUS/TLS, we performed a yeast two-hybrid screening and found that protein arginine methyltransferase 1 (PRMT1) is one of binding partners primarily in the nucleus. In vitro and in vivo methylation assays showed that FUS/TLS could be methylated by PRMT1. The modulation of arginine methylation levels by a general methyltransferase inhibitor or conditional over-expression of PRMT1 altered slightly the nucleus-cytoplasmic ratio of FUS/TLS in cell fractionation assays. Although co-localized primarily in the nucleus in normal condition, FUS/TLS and PRMT1 were partially recruited to the cytoplasmic granules under oxidative stress, which were merged with stress granules (SGs) markers in SH-SY5Y cell. C-terminal truncated form of FUS/TLS (FUS-dC), which lacks C-terminal nuclear localization signal (NLS), formed cytoplasmic inclusions like ALS-linked FUS mutants and was partially co-localized with PRMT1. Furthermore, conditional over-expression of PRMT1 reduced the FUS-dC-mediated SGs formation and the detergent-insoluble aggregates in HEK293 cells. These findings indicate that PRMT1-mediated arginine methylation could be implicated in the nucleus-cytoplasmic shuttling of FUS/TLS and in the SGs formation and the detergent-insoluble inclusions of ALS-linked FUS/TLS mutants.
    PLoS ONE 11/2012; 7(11):e49267. DOI:10.1371/journal.pone.0049267 · 3.23 Impact Factor
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    • "Control of plasma ADMA level is mainly by degradation by the DDAH1 enzyme, which is abundant in liver and kidney (Palm et al., 2007; Sasser et al., 2009). ADMA is made by PRMT1, a class of enzymes that methylate amino acids (including arginine) while they are incorporated into intact proteins (Nicholson et al., 2009). The free (active) ADMA is released by proteolysis. "
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    ABSTRACT: Age-dependent renal damage is influenced by genetic background and the Fisher344xBrown Norway (F344xBN) rat is resistant to glomerular injury. In vulnerable strains, a fall in renal nitric oxide synthase (NOS) contributes to age-dependent renal damage. Here, we investigated renal NOS in young (3 months) and old (30 months) male F344xBN to test the hypothesis that renal NOS is maintained in "protected" strains. We also examined if 6 months of renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibition (ACEI) and angiotensin receptor blockade (ARB) provides further benefit in these "protected" old rats. Aging increased tubulointerstitial injury but glomerular sclerosis was minimal and NOS and superoxide dismutase abundance increased. There was no change in the NOS inhibitor, ADMA (asymmetric dimethylarginine) or its regulatory enzymes. RAS blockade with ARB protected against tubulointerstitial injury and increased nNOSα, but ACEI, which also increased nNOSα, had no protective effect on the tubulointerstitium. We conclude that the glomerular sclerosis-resistant aged male F344xBN rat maintains renal NOS, thus reinforcing our hypothesis that progressive glomerular injury is related to renal NOS deficiency. The tubulointerstitial injury seen with aging is reversed with 6 months of ARB but not ACEI and is not associated with renal NOS.
    Mechanisms of ageing and development 11/2010; 132(1-2):1-7. DOI:10.1016/j.mad.2010.10.004 · 3.40 Impact Factor
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