Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs

Dhar, Surbhi; Vemulapalli, Vidyasiri; Patananan, Alexander N.; Huang, Grace L.; Lorenzo, Alessandra Di; Richard, Stéphane; Comb, Michael J.; Guo, Ailan; Clarke, Steven; Bedford, Mark T.

doi:10.1038/srep01311

Cited by 199 publications

(213 citation statements)

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“…PRMT1 suppression may both induce antitumor effects and proliferation depending on the cell type. Three types of arginine methylation have been reported; monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), with PRMT1 accounting for more than 90 % of the AMDA type of methylation [20]. The loss of PRMT1 increased the levels of MMA and SDMA, and PRMT1 is transported between the nucleus and cytoplasm depending on the methylation status of substrate proteins in several cells [21].…”

Section: Discussionmentioning

confidence: 99%

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

et al. 2015

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Background Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. Methods We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. Results PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. Conclusion Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

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Section: Discussionmentioning

confidence: 99%

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

et al. 2015

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“…S2), as well as a reduction in proteins with symmetrically dimethylated arginine modifications in Prmt5 conditional knockout forelimbs ( Fig. 1H) (Dhar et al, 2013). Whereas Prx1Cre +/− ; Prmt5 c/+ littermates appeared normal, Prx1Cre +/− ; Prmt5 c/c mice (hereafter referred to as Prmt5 cKO) had severe, distinctive forelimb defects (Fig.…”

Section: Prmt5 Conditional Mutants Have Truncated Skeletal Elements Amentioning

confidence: 99%

“…Limb buds were homogenized in RIPA buffer (5 mM Tris pH 7.5, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% Triton X-100) containing complete mini EDTA-free protease inhibitor and PhosphoSTOP (Roche (Dhar et al, 2013). Membranes were then incubated in donkey anti-rabbit secondary antibody (1:2000, 711-035-152 Jackson ImmunoResearch) for 1 h at room temperature and developed using ECL Prime Western Blotting Detection Reagent (GE Healthcare).…”

Section: Western Blots and Immunostainingmentioning

confidence: 99%

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

Norrie

et al. 2016

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During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis.

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“…substrate specificity and is responsible for the majority (∼85%) of total protein R methylation in cultured cells (19), was downregulated by both single and repeated cocaine injections. Prmt2, Prmt5, Prmt6, Prmt8, and Prmt9 (20, 21) were down-regulated by repeated cocaine administration, but not by a single cocaine exposure.…”

Section: Significancementioning

confidence: 99%

Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanismssuch as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.histone arginine (R) methylation | drug addiction | medium spiny neurons | ChIP-seq | Src R epeated cocaine exposure is marked by persistent changes in gene expression within the nucleus accumbens (NAc), a central component of the brain's reward circuitry (1, 2). Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3-11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.The methylation of R residues is catalyzed by the protein R methyltransferase (PRMT) family of enzymes, which can generate different methylated R states with diverse functional consequences, including monomethylarginine (MMA) and dimethylarginine (DMA) residues, the latter of which can be either asymmetric (aDMA) or symmetric (sDMA). PRMTs that catalyze aDMA are designated type I, and those that generate sDMA are designated type II (12, 13). Histone tails are prime targets for these PRMTs, and R methylation induces alterations in chromatin architecture, either condensing or relaxing its structure, thereby creating binding sites for regulatory proteins that contain specialized binding domains (14, 15).PRMT6, a nuclear enzyme that modifies histone tails, is the primary enzyme responsible for asymmetric dimethylation of R2 on histone H3 (H3R2me2a) in mammalian cells (14,16). The H3R2me2a mark is thought to be repressive in nature because of...

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Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs

Cited by 199 publications

References 19 publications

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

Histone arginine methylation in cocaine action in the nucleus accumbens

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