The Structure and Functions of PRMT5 in Human Diseases

Motolani, Aishat; Martin, Matthew; Sun, Mengyao; Lü, Tao

doi:10.3390/life11101074

Cited by 32 publications

(31 citation statements)

References 96 publications

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“…The protein arginine methyltransferase 5(PRMT5) is responsible for regulation of multiple biological processes including transcription, RNA splicing, metabolic signaling, differentiation, and spliceosome assembly [8,9]. PRMT5 always complexed with the WD-repeat protein MEP50 and binding to the catalytic site to produce methylarginine of histone or target protein [10,11].…”

Section: Introductionmentioning

confidence: 99%

MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma

Zhu

et al. 2022

Cell Death Dis

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Angiogenesis is considered as an important process in tumor growth, metastasis of hepatocellular carcinoma (HCC) and associated with cancer progression, suggesting that an important research and development field of clinical molecular targeted drugs for HCC. However, the molecular mechanisms underlying tumor angiogenesis in HCC remains elusive. In the current study, we demonstrate that upregulation of AMYB proto-oncogene-like 1 (MYBL1) was associated with high endothelial vessel (EV) density and contributed to poor prognosis of HCC patient. Functionally, MYBL1 overexpressing enhanced the capacity of HCC cells to induce tube formation, migration of HUVECs, neovascularization in CAMs, finally, enhanced HCC cells metastasis, while silencing MYBL1 had the converse effect. Furthermore, HCC cells with high MYBL1 expression were more resistance to sorafenib treatment. We observed that CD31 staining was significantly increased in tumors formed by MYBL1-overexpressing cells but decreased in MYBL1-silenced tumors. Mechanistically, MYBL1 binds to the ANGPT2 promoter and transcriptionally upregulate ANGPT2 mRNA expression. Strikingly, treatment with monoclonal antibody against ANGPT2 significantly inhibited the growth of MYBL1-overexpressing tumors and efficiently impaired angiogenesis. Furthermore, the histone post-translational factors: protein arginine methyltransferase 5 (PRMT5), MEP50, and WDR5 were required for MYBL1-mediated ANGPT2 upregulation. Importantly, we confirmed the correlation between MYBL1 and ANGPT2 expression in a large cohort of clinical HCC samples and several published datasets in pancreatic cancer, esophageal carcinoma, stomach adenocarcinoma, and colon cancer. Our results demonstrate that MYBL1 upregulated the ANGPT2 expression, then induced angiogenesis and confer sorafenib resistance to HCC cells, and MYBL1 may represent a novel prognostic biomarker and therapeutic target for patients with HCC.

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Section: Introductionmentioning

confidence: 99%

MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma

Zhu

et al. 2022

Cell Death Dis

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“…1 The pivotal role of PRMT5 in diverse types of cancers and cardiovascular and neurodegenerative diseases calls for a detailed understanding of the activity, function, and regulation of this enzyme. 1,2 Inhibition of the enzymatic activity of PRMT5 is a therapeutic strategy that is currently being explored for cancer treatment, with various compounds being tested in clinical trials. 3,4 PRMT5 is composed of three domains: a Rossmann fold, a β-barrel, and a TIM barrel.…”

Section: ■ Introductionmentioning

confidence: 99%

“…9 PRMT5's function, activity, and substrate specificity are regulated through post-translational modifications of the enzyme, expression of several miRNAs, and interaction with pertinent adaptor proteins. 1 These adaptor proteins include the aforementioned MEP50 aiding in histone tail methylation, 7,8,10 RioK1, which recruits nucleolin as a substrate, 11 pICln, which connects the enzyme to Sm proteins, 12,13 and COPR5, which enables recruitment to chromatin and preferential methylation of histone H4. 14 Being able to selectively modulate one of the PRMT5 PPIs would allow one to inhibit the methylation of only a subset of its targets.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Protein arginine methyltransferase 5 (PRMT5) is a prominent epigenetic regulator with a critical function in cellular development, growth, splicing, DNA damage response, signaling, trafficking, and other biological processes . The pivotal role of PRMT5 in diverse types of cancers and cardiovascular and neurodegenerative diseases calls for a detailed understanding of the activity, function, and regulation of this enzyme. , Inhibition of the enzymatic activity of PRMT5 is a therapeutic strategy that is currently being explored for cancer treatment, with various compounds being tested in clinical trials. , …”

Section: Introductionmentioning

confidence: 99%

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Development of Macrocyclic PRMT5–Adaptor Protein Interaction Inhibitors

Krzyzanowski

Esser

Willaume³

et al. 2022

J. Med. Chem.

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The PRMT5-MEP50 methyltransferase is a major target for anticancer drug discovery, and modulators of its interactions with different regulatory proteins are in high demand because they modulate PRMT5 substrate selectivity. We describe a strategy for the development of a PRMT5/adaptor protein PPI inhibitor, which includes the design and synthesis of macrocyclic peptides based on the motif for the interaction of PRMT5 with its adaptor protein RioK1. After the initial exploration of different macrocycle sizes and cyclization linkages, analysis of a peptide library identified hot spots for the variation of the amino acid structure. The incorporation of nonproteinogenic amino acids into the macrocyclic peptide led to a potent cyclic PRMT5 binding peptide (K i = 66 nM), which selectively inhibits the interaction of PRMT5 with the adaptor proteins RioK1 and pICln (IC 50 = 654 nM) but not with the alternative adaptor protein MEP50. The inhibitor is a promising tool for further biological investigation of this intriguing protein interface.

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“…Cura and Cavarelli [ 23 ] provided a review on PRMT2, focusing on its structural features and its role in splicing. Motolani et al [ 24 ] reviewed the functionally versatile major type II protein arginine methyltransferase PRMT5, focusing on its role in various human diseases such as various types of cancers, diabetes, cardiovascular, and neurodegenerative diseases. Gupta et al [ 25 ] presented the current literature status of PRMT6 and covered topics such as structural features, kinetic mechanism, epigenetic functions, and non-histone substrates of PRMT6.…”

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confidence: 99%