The Role of PRMT1 in Cellular Regulation and Disease: Insights into Biochemical Functions and Emerging Inhibitors for Cancer Therapy DOI Creative Commons
Shenglin Ma, Shuhua Yi,

Hui Zou

et al.

European Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 204, P. 106958 - 106958

Published: Nov. 7, 2024

Protein Arginine Methyltransferase 1 (PRMT1), a primary protein arginine methyltransferase, plays pivotal role in cellular regulation, influencing processes such as gene expression, signal transduction, and cell differentiation. Dysregulation of PRMT1 has been linked to the development various cancers, establishing it key target for therapeutic intervention. This review synthesizes biochemical characteristics, structural domains, functional mechanisms PRMT1, focusing on its involvement tumorigenesis. Additionally, efficacy emerging inhibitors potential cancer therapies are examined. By employing molecular modeling insights from existing literature, this posits that targeting PRMT1's methyltransferase activity could disrupt progression, providing valuable future drug development.

Language: Английский

Therapeutic Potential of PRMT1 as a Critical Survival Dependency Target in Multiple Myeloma DOI Open Access

Tabish Hussain,

Sharad Awasthi,

Fauzia Shahid

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Abstract Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and the second most prevalent hematological malignancy worldwide. Development drug resistance disease relapse significantly impede success MM treatment, highlighting critical need to discover novel therapeutic targets. In custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as top hit, revealing it potential vulnerability survival dependency in cells. PRMT1, major Type I PRMT enzyme, catalyzes asymmetric transfer methyl groups arginine residues, influencing gene transcription protein function through post-translational modification. Dysregulation or overexpression PRMT1 has been observed various malignancies including linked chemoresistance. Treatment with inhibitor GSK3368715 resulted dose-dependent reduction cell across panel lines. This was accompanied by reduced levels dimethylation (ADMA) increased monomethylation (MMA) Cell cycle analysis revealed an accumulation G0/G1 phase S upon treatment. Additionally, inhibition led significant downregulation genes involved proliferation, replication, response (DDR), likely inducing genomic instability impairing tumor growth. supported Reverse Phase Array (RPPA) analyses, which proteins associated regulation DDR pathways. Overall, our findings indicate that critically depend on for survival, treating MM.

Language: Английский

Citations

0
Oligomerization of protein arginine methyltransferase 1 and its effect on methyltransferase activity and substrate specificity DOI Creative Commons
Vincent Rossi,

Sarah E. Nielson,

Ariana Ortolano

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 33(8)

Published: July 18, 2024

Abstract Proper protein arginine methylation by methyltransferase 1 (PRMT1) is critical for maintaining cellular health, while dysregulation often associated with disease. How the activity of PRMT1 regulated therefore paramount, but not clearly understood. Several studies have observed higher order oligomeric species PRMT1, it unclear if these exist at physiological concentrations and there confusion in literature about how oligomerization affects activity. We sought to determine which are physiologically relevant, quantitatively correlate specific oligomer forms. Through quantitative western blotting, we determined that available a variety human cell lines sub‐micromolar low micromolar range. Isothermal spectral shift binding data were modeled monomer/dimer/tetramer equilibrium an EC 50 tetramer dissociation ~20 nM. A combination sedimentation velocity Native polyacrylamide gel electrophoresis experiments directly confirmed major would be dimers tetramers. Surprisingly, dimeric variant similar wild type, tetrameric some purified substrates, dimer forms show differences catalytic efficiencies substrate specificity other substrates. Our results define paradigm biophysical characteristics poised support vivo, suggest state could used regulate specificity.

Language: Английский

Citations

4
PRMT1‐mediated BRD4 arginine methylation and phosphorylation promote partial epithelial–mesenchymal transformation and renal fibrosis DOI Open Access

C.-L. Xiong,

Haishan Chen,

Baoting Su

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 7, 2025

Bromodomain-containing protein 4 (BRD4) plays a vital role in fibrosis of various organs. However, the underlying mechanism BRD4 renal remains unclear. To construct vitro and vivo models fibrosis, TCMK-1 cells were subjected to TGF-β1 treatment mice UUO surgery adenine induction. IP assay was used for arginine asymmetric dimethylation (ADMA) level, ubiquitination degradation Snail, acetylation level Snail test. Co-IP validate interactions BRD4, methyltransferase-1 (PRMT1), Snail. HE staining Masson morphological examination tissue. abnormally overexpressed during fibrosis. TGF-β1-induced partial epithelial-mesenchymal transition (pEMT) could be inhibited by silencing. PRMT1 mediated ADMA enhance phosphorylation its stability. attenuated overexpression an acetylation-dependent manner cells. Furthermore, inhibitor abolished overexpression-induced pEMT TGF-β1-treated reversed silencing-induced inhibition pEMT. What's more, reduction methylation expression alleviate induction mice. Collectively, PRMT1-mediated promoted through regulation expression.

Language: Английский

Citations

0
Overview of PRMT1 Modulators: Inhibitors and Degraders DOI
Jun Wu,

Deping Li,

Li‐Fang Wang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116887 - 116887

Published: Sept. 20, 2024

Language: Английский

Citations

3
CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism DOI Creative Commons
Xin Zhang, Yajun Duan, Li Su

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114662 - 114662

Published: Aug. 23, 2024

Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation polyunsaturated phospholipids. However, much remains unknown about the regulators ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as crucial promoter We find that PRMT1 decreases expression solute carrier family 7 member 11 (SLC7A11) to limit abundance intracellular glutathione (GSH). Moreover, show interacts with ferroptosis suppressor (FSP1), GSH-independent suppressor, inhibit membrane localization and enzymatic activity FSP1 through dimethylation at R316, thus reducing CoQ10H2 content inducing sensitivity. Importantly, depletion or pharmacological inhibition in mice prevents ferroptotic events liver improves overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest key regulator potential target for antiferroptosis therapeutics.

Language: Английский

Citations

2
Metformin suppresses gastric cancer progression by disrupting the STAT1-PRMT1 axis DOI

Kaiqing Wang,

Yanyan Chen, Meimei Zhang

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 226, P. 116367 - 116367

Published: June 12, 2024

Language: Английский

Citations

1
The Role of PRMT1 in Cellular Regulation and Disease: Insights into Biochemical Functions and Emerging Inhibitors for Cancer Therapy DOI Creative Commons
Shenglin Ma, Shuhua Yi,

Hui Zou

et al.

European Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 204, P. 106958 - 106958

Published: Nov. 7, 2024

Protein Arginine Methyltransferase 1 (PRMT1), a primary protein arginine methyltransferase, plays pivotal role in cellular regulation, influencing processes such as gene expression, signal transduction, and cell differentiation. Dysregulation of PRMT1 has been linked to the development various cancers, establishing it key target for therapeutic intervention. This review synthesizes biochemical characteristics, structural domains, functional mechanisms PRMT1, focusing on its involvement tumorigenesis. Additionally, efficacy emerging inhibitors potential cancer therapies are examined. By employing molecular modeling insights from existing literature, this posits that targeting PRMT1's methyltransferase activity could disrupt progression, providing valuable future drug development.

Language: Английский

Citations

0