Affinage

PRMT5

Protein arginine N-methyltransferase 5 · UniProt O14744

Length
637 aa
Mass
72.7 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRMT5 is the principal type II protein arginine methyltransferase, catalyzing symmetric dimethylation of arginine residues on histones and a broad spectrum of non-histone substrates to regulate mRNA splicing, chromatin silencing, signal transduction, DNA repair, and metabolic homeostasis. It functions as a hetero-octameric complex with MEP50/WDR77 and achieves substrate selectivity through modular adaptor proteins (pICln/CLNS1A, RIOK1, COPR5) recruited via a conserved peptide-binding motif; disruption of this adaptor interface impairs spliceosomal Sm protein methylation, causing widespread intron retention and splicing defects critical for hematopoietic stem cell maintenance and germ cell development (PMID:34358446, PMID:30811983, PMID:25457166). PRMT5 methylates diverse signaling proteins—including AKT1-R391 (enabling membrane translocation and kinase activation), cGAS-R124 (blocking cytosolic DNA sensing), 53BP1 (stabilizing for NHEJ repair), GPX4-R152 (preventing ubiquitin-mediated degradation and ferroptosis), and MST2 (suppressing Hippo pathway activation)—thereby integrating arginine methylation into oncogenic, immune, and stress-response circuits (PMID:34103528, PMID:33762328, PMID:32759981, PMID:40033101, PMID:37905571). Its enzymatic activity is negatively regulated by the metabolite methylthioadenosine (MTA, accumulating in MTAP-deleted cancers), by Src-mediated Y324 phosphorylation that blocks SAM binding, and by LKB1-mediated T139/T144 phosphorylation that disrupts adaptor interactions (PMID:26912360, PMID:32759981, PMID:30289978).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2009 Medium

    Establishing that PRMT5 is required for cell cycle progression answered whether this methyltransferase has essential proliferative functions beyond chromatin modification, linking it to G1 arrest and eIF4E-dependent translational control.

    Evidence Inducible shRNA knockdown with cell-cycle analysis and eIF4E rescue in human cell lines

    PMID:19528079

    Open questions at the time
    • Single lab; the mechanism connecting PRMT5 to eIF4E expression was not fully resolved
    • Whether PRMT5 directly methylates a translational regulator upstream of eIF4E was not tested
  2. 2011 Medium

    Identification of COPR5 as a targeting adaptor that recruits PRMT5 to specific promoters (p21, myogenin) established the principle that PRMT5 requires accessory proteins for substrate selectivity at chromatin.

    Evidence COPR5 siRNA in C2C12 myoblasts with ChIP showing loss of PRMT5 recruitment and impaired muscle regeneration in vivo

    PMID:22193545

    Open questions at the time
    • How many other adaptor proteins exist was unknown
    • Structural basis of the COPR5-PRMT5 interaction was not resolved
  3. 2014 High

    Demonstrating that PRMT5 translocates to the nucleus in primordial germ cells to deposit H2A/H4R3me2s on transposons during DNA hypomethylation revealed a critical epigenetic safeguard mechanism, as PRMT5 loss caused transposon derepression, DNA damage, and sterility.

    Evidence Conditional knockout (Blimp1-Cre) in mouse PGCs with ChIP for H2A/H4R3me2s and live imaging of PRMT5 translocation

    PMID:25457166

    Open questions at the time
    • Whether PRMT5-mediated transposon silencing operates in somatic cells was not tested
    • The signal triggering PRMT5 nuclear translocation was not identified
  4. 2015 Medium

    Discovery that PRMT5 methylates the D2 dopamine receptor's intracellular loop to enhance Gi-coupled cAMP inhibition extended PRMT5 substrates beyond nuclear and spliceosomal targets to membrane-resident GPCRs.

    Evidence In vitro methylation assay, receptor arginine mutagenesis, cAMP signaling in HEK293T, and C. elegans behavioral genetics

    PMID:26554819

    Open questions at the time
    • Whether PRMT5 methylates other GPCRs was not explored
    • In vivo mammalian validation of receptor methylation was lacking
  5. 2016 High

    Three independent groups demonstrated that MTAP deletion causes MTA accumulation that selectively inhibits PRMT5, creating a targetable synthetic vulnerability — this was the foundational discovery for PRMT5-directed cancer therapy in MTAP-null tumors.

    Evidence Biochemical methyltransferase profiling with MTA, metabolomics, shRNA screens, and MTAP reconstitution in isogenic cell lines across three labs

    PMID:26912360 PMID:26912361 PMID:27068473

    Open questions at the time
    • The therapeutic window for PRMT5 inhibition in MTAP-intact vs MTAP-deleted contexts was not yet defined clinically
    • Which PRMT5 substrates are most affected by partial inhibition was unclear
  6. 2016 Medium

    Showing that c-Myc recruits PRMT5-MEP50 to deposit H4R3me2s at target gene promoters established PRMT5 as a Myc transcriptional co-activator, while separately PRMT5 was linked to Wnt/β-catenin signaling in CML via DVL3 stabilization.

    Evidence Co-IP, ChIP for H4R3me2s at Myc targets in glioblastoma cells; shRNA and small-molecule inhibition in BCR-ABL CML model with serial replating

    PMID:26563484 PMID:27643437

    Open questions at the time
    • Whether PRMT5 directly methylates DVL3 was not shown
    • The generality of Myc-PRMT5 co-activation across cancer types was not tested
  7. 2018 Medium

    LKB1 was identified as a negative regulator that phosphorylates PRMT5 at T139/T144, disrupting MEP50 and adaptor binding to suppress methyltransferase activity — the first kinase shown to directly regulate PRMT5 catalytic function.

    Evidence In vitro kinase assay, site-directed mutagenesis (T139/144A), PRMT5 activity measurement in mammary epithelial cells

    PMID:30289978

    Open questions at the time
    • In vivo significance of LKB1-PRMT5 axis in tumor suppression was not demonstrated
    • Whether other kinases target this region was unknown
  8. 2019 High

    Multiple conditional knockout studies converged on PRMT5-mediated Sm protein methylation as essential for splicing fidelity: PRMT5 loss causes intron retention in DNA repair transcripts in HSCs and germ cells, leading to p53-dependent exhaustion and apoptosis.

    Evidence Conditional PRMT5 KO in HSCs and B cells with RNA-seq splicing analysis, γH2AX quantification, and p53 depletion rescue

    PMID:25519955 PMID:30604754 PMID:30811983

    Open questions at the time
    • Which specific splicing events are direct versus indirect consequences of Sm protein hypomethylation was not fully resolved
    • Whether splicing-independent functions contribute to HSC loss was not excluded
  9. 2019 High

    PRMT5 was shown to methylate DDX5 at RGG/RG motifs, enabling DDX5-XRN2 interaction required for R-loop resolution at transcription terminators — directly linking PRMT5 to genome stability through a non-histone, non-spliceosomal mechanism.

    Evidence In vitro R-loop resolution assay with recombinant DDX5, DRIP-qPCR, and γH2AX foci in PRMT5-depleted cells

    PMID:31267554

    Open questions at the time
    • Whether other DEAD-box helicases are similarly regulated by PRMT5 was not tested
    • The relative contribution of R-loop accumulation versus splicing defects to PRMT5-loss phenotypes was unclear
  10. 2019 High

    Global proteomic profiling defined the PRMT5 substrate landscape, revealing a preference for Gly-Arg-Gly (GRG) motifs and hundreds of substrates spanning chromatin, splicing, and signaling — providing a systematic framework for understanding PRMT5's pleiotropic functions.

    Evidence SILAC-based immunoenrichment of methyl peptides with PRMT5 inhibitor treatment and in vitro methylation validation

    PMID:30940768

    Open questions at the time
    • Functional consequences of methylation for most identified substrates remain unexplored
    • Substrate selectivity in different tissues was not addressed
  11. 2020 Medium

    Src kinase was identified as phosphorylating PRMT5-Y324 to block SAM binding and suppress methyltransferase activity, with downstream consequences for 53BP1 methylation/stabilization and NHEJ repair — establishing a signaling axis that couples growth factor signaling to DNA repair capacity.

    Evidence In vitro kinase assay, SAM binding assay, NHEJ repair assay, 53BP1 stability measurement with Y324 mutagenesis

    PMID:32759981

    Open questions at the time
    • Whether Y324 phosphorylation is dynamically regulated during the DNA damage response in vivo was not shown
    • Other substrates affected by Src-mediated PRMT5 inhibition were not identified
  12. 2020 Medium

    PRMT5 was found to suppress innate immune signaling by methylating IFI16, attenuating the cGAS/STING pathway and IFN production, while also repressing NLRC5-dependent MHC-I presentation — establishing PRMT5 as a dual immune checkpoint in tumor immune evasion.

    Evidence PRMT5 knockdown/inhibitor treatment with immune signaling readouts in immunocompetent and immunocompromised mouse melanoma models

    PMID:32641491

    Open questions at the time
    • Whether IFI16 methylation directly blocks STING interaction was not structurally resolved
    • The relative contribution of IFI16 methylation versus NLRC5 repression to immune evasion was not dissected
  13. 2021 High

    Structural resolution of the PRMT5 adaptor-binding interface revealed a conserved peptide motif used by pICln, RIOK1, and COPR5 to recruit distinct substrate classes, providing the structural basis for PRMT5's modular substrate selectivity and explaining why adaptor disruption phenocopies splicing defects and MTAP-null vulnerability.

    Evidence Crystal structure of PRMT5-adaptor interface, genetic perturbation of binding motif, RNA-seq for splicing in adaptor mutants

    PMID:34358446

    Open questions at the time
    • Whether additional undiscovered adaptors exist was not addressed
    • How adaptor competition is regulated in different cell types was not resolved
  14. 2021 High

    PRMT5 methylation of AKT1-R391 was shown to relieve the PH-in autoinhibitory conformation, enabling membrane translocation and activation by PDK1/mTORC2 — revealing arginine methylation as a previously unrecognized activation step in PI3K-AKT signaling.

    Evidence In vitro methylation, R391A mutagenesis, membrane translocation assay, xenograft tumor suppression; independently confirmed

    PMID:34103528 PMID:35803962

    Open questions at the time
    • Whether PRMT5-AKT1 methylation is regulated in a stimulus-dependent manner was not established
    • Contribution of AKT1 methylation relative to lipid-mediated activation in different tissues was unclear
  15. 2021 Medium

    Discovery that PRMT5 methylates cGAS-R124 to directly block DNA binding provided a second, distinct mechanism (beyond IFI16) for PRMT5-mediated suppression of cytosolic DNA sensing and antiviral innate immunity.

    Evidence Co-IP, in vitro methylation, DNA-binding assay, PRMT5 inhibitor in HSV-1 infection

    PMID:33762328

    Open questions at the time
    • Whether cGAS methylation occurs constitutively or is induced upon infection was not clarified
    • Single lab; independent replication needed
  16. 2022 Medium

    PRMT5 methylation of MTHFD1-R173 enhancing NADPH production under anchorage-independent conditions linked PRMT5 to one-carbon metabolism and anoikis resistance, expanding its substrate repertoire to metabolic enzymes.

    Evidence CRISPR metabolic screen, in vitro methylation, NADPH measurement, in vivo metastasis model

    PMID:35798877

    Open questions at the time
    • Whether this occurs in normal physiology or only under cancer-specific conditions was unknown
    • Single lab
  17. 2023 Medium

    Multiple studies identified new PRMT5 substrates (SMAD4-R361, MST2-R461/467, ENO1-R9, G3BP2-R468, ALKBH5-R316, KLF5-R57) with site-specific mutagenesis, collectively demonstrating that PRMT5-mediated methylation frequently modulates substrate ubiquitination, dimerization, or protein-protein interactions to control TGF-β, Hippo, glycolysis, lipogenesis, and m6A RNA modification pathways.

    Evidence In vitro methylation assays, site-directed mutagenesis, ubiquitination/stability assays, and in vivo tumor models across multiple studies

    PMID:33972717 PMID:36878903 PMID:36991117 PMID:36999124 PMID:37905571 PMID:39781264

    Open questions at the time
    • Most substrates validated in single labs; independent replication is needed for each
    • Whether these substrates are methylated simultaneously or in a context-dependent manner is unknown
    • Structural basis for PRMT5 recognition of most non-GRG substrates is not resolved
  18. 2025 High

    PRMT5 methylation of GPX4-R152 was shown to block Cullin1-FBW7-mediated ubiquitination and degradation of GPX4, directly linking PRMT5 to ferroptosis regulation and revealing a therapeutic strategy combining PRMT5 and ferroptosis inducers.

    Evidence In vitro methylation, R152 mutagenesis, GPX4 half-life and ubiquitination assays, Co-IP with Cullin1-FBW7, in vivo tumor models

    PMID:40033101

    Open questions at the time
    • Whether GPX4 methylation is dynamically regulated by oxidative stress was not tested
    • The adaptor protein mediating PRMT5-GPX4 interaction was not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how adaptor competition and cell-type-specific substrate selection are regulated in vivo; the relative contributions of splicing versus non-histone substrate methylation to PRMT5 essentiality in different tissues; and whether the therapeutic window for PRMT5 inhibition differs for splicing-dependent versus signaling-dependent tumor dependencies.
  • No systematic in vivo mapping of adaptor-dependent substrate hierarchies
  • No structural model of full-length PRMT5 bound to non-canonical substrates
  • Clinical biomarkers distinguishing splicing-dependent from signaling-dependent PRMT5 addiction are undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 14 GO:0140096 catalytic activity, acting on a protein 9 GO:0042393 histone binding 5
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-8953854 Metabolism of RNA 5 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 1
Partners
CLNS1ACOPR5DDX5EZH2OXR1RIOK1SMAD3WDR77
Complex memberships
PRMT5-MEP50 hetero-octamerPRMT5-MEP50-COPR5PRMT5-MEP50-RIOK1PRMT5-MEP50-pICln

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 MTAP deletion leads to accumulation of methylthioadenosine (MTA), which directly and selectively inhibits PRMT5 enzymatic activity, creating a hypomorphic PRMT5 state that sensitizes cells to further PRMT5 inhibition. PRMT5 functions in complex with its binding partner WDR77/MEP50. Biochemical profiling of methyltransferase enzyme panel with MTA, metabolomic studies, shRNA screens, isogenic cell line comparisons, MTAP reconstitution experiments Science / Cell reports High 26912360 26912361 27068473
2021 PRMT5 uses an evolutionarily conserved peptide binding motif to recruit substrate adaptor proteins (CLNS1A/pICln, RIOK1, and COPR5); this adaptor interface is necessary and sufficient for methylation of adaptor-recruited substrates including spliceosomal Sm proteins, histones, and ribosomal complexes. Disruption of this interface impairs Sm spliceosome activity and causes intron retention, and impairs growth of MTAP-null tumor cells. Structural resolution of PRMT5-adaptor interface, genetic perturbation, RNA-seq for splicing, biochemical interaction assays Molecular cell High 34358446
2019 PRMT5 binds and methylates the RGG/RG motif of DDX5 helicase; this methylation is required for DDX5 interaction with the XRN2 exoribonuclease and for resolution of RNA:DNA hybrids (R-loops) at transcriptional termination regions. PRMT5-deficient cells accumulate R-loops and γH2AX foci. In vitro R-loop resolution assay with recombinant DDX5, DRIP-qPCR, Co-IP, γH2AX immunofluorescence, PRMT5 KD cells The EMBO journal High 31267554
2021 PRMT5 catalyzes symmetric dimethylation of AKT1 at arginine 391 (R391), which cooperates with PIP3 to relieve the PH-in conformation, enabling AKT1 translocation to the plasma membrane and subsequent phosphorylation/activation by PDK1 and mTORC2. Deficiency in AKT1-R391 methylation suppresses AKT1 kinase activity and tumorigenesis. In vitro methylation assay, site-directed mutagenesis (R391A), membrane translocation assay, Co-IP with PDK1/mTORC2, xenograft tumor models Nature communications High 34103528 35803962
2014 PRMT5 translocates from the cytoplasm to the nucleus during global DNA demethylation in primordial germ cells and preimplantation embryos; nuclear PRMT5 is required for the repressive H2A/H4R3me2s chromatin modification on LINE1 and IAP transposons, silencing these elements during DNA hypomethylation. Loss of PRMT5 in early PGCs causes upregulation of transposons, DNA damage response activation, and complete sterility. Conditional knockout (Blimp1-Cre), chromatin immunofluorescence, H2A/H4R3me2s ChIP, live imaging of PRMT5 localization Molecular cell High 25457166
2009 PRMT5 is required for cell-cycle progression; PRMT5 knockdown triggers G1 arrest and prevents p53 protein synthesis by regulating expression of translation initiation factor eIF4E. Growth suppression upon PRMT5 knockdown is p53-independent but eIF4E-dependent. Inducible shRNA knockdown, cell-cycle analysis, immunoblotting for eIF4E and p53, rescue experiments Nucleic acids research Medium 19528079
2019 PRMT5 arginine methylation of the Sm spliceosomal proteins is essential for regulating splicing fidelity in primordial germ cells and B cells; PRMT5 loss alters the spliced RNA repertoire and causes intron retention, impacting DNA repair gene expression in hematopoietic stem cells. Conditional KO, RNA-seq splicing analysis, proteomics Cell reports / Nature communications / The EMBO journal High 25519955 30604754 30811983
2019 CDK4/6 inhibitor palbociclib indirectly suppresses PRMT5 activity, which alters pre-mRNA splicing of MDM4 leading to decreased MDM4 protein, p53 activation, and p21 induction inhibiting CDK2. Loss of palbociclib's ability to regulate the PRMT5-MDM4 splicing axis drives resistance. Splicing assays, PRMT5 inhibitor (GSK3326595) combination studies, immunoblotting, resistance cell line analysis PNAS Medium 31439820
2020 PRMT5 methylates IFI16 (and its murine homolog IFI204), attenuating cGAS/STING pathway-mediated cytosolic DNA-induced IFN and chemokine expression in melanoma cells. PRMT5 also inhibits NLRC5 transcription to suppress MHC class I antigen presentation. PRMT5 KD/inhibition (GSK3326595), immunocompetent vs immunocompromised mouse models, IFI16 methylation assays Science translational medicine Medium 32641491
2021 PRMT5 directly binds and catalyzes symmetric dimethylation of cGAS at arginine 124 (R124), blocking the DNA-binding ability of cGAS and attenuating cGAS-mediated antiviral immune response. Co-IP, in vitro methylation assay, DNA-binding assay, PRMT5 inhibitor treatment in HSV-1 infection model Science advances Medium 33762328
2020 PRMT5 is phosphorylated at tyrosine 324 (Y324) by Src kinase, which suppresses PRMT5 activity by preventing binding to the methyl donor SAM. PRMT5 activity promotes non-homologous end joining (NHEJ) DNA repair by methylating and stabilizing 53BP1; Src-mediated phosphorylation of PRMT5 blocks NHEJ and leads to apoptotic cell death after DNA damage. In vitro kinase assay, SAM binding assay, NHEJ repair assay, 53BP1 methylation and stability assays, Y324 mutagenesis Communications biology Medium 32759981
2016 PRMT5 forms a positive feedback loop with BCR-ABL in CML; PRMT5 inhibition abrogates the Wnt/β-catenin pathway in CML leukemia stem cells by depleting DVL3, impairing self-renewal capacity. shRNA KD, small-molecule inhibitor (PJ-68), murine retroviral BCR-ABL CML model, LTC-IC assay, serial replating Journal of Clinical Investigation Medium 27643437
2018 PRMT5 is phosphorylated by LKB1 at residues T132, T139, and T144 within its TIM-Barrel domain; T139/144 phosphorylation drastically decreases PRMT5 methyltransferase activity, at least partly by disrupting interaction with regulatory proteins MEP50, pICln, and RioK1. PRMT5 and LKB1 directly interact in the cytoplasm of mammary epithelial cells. Co-IP, in vitro kinase assay, site-directed mutagenesis (T139/144A), PRMT5 activity assay, LKB1 modulation International journal of cancer Medium 30289978
2023 PRMT5 interacts with SMAD4 and methylates it at arginine 361 (R361) upon TGF-β1 treatment, promoting SMAD complex formation and nuclear import, thereby activating TGF-β signaling and EMT in colorectal cancer. R361 mutation diminishes PRMT5/TGF-β-induced metastasis. Mass spectrometry, Co-IP, immunofluorescence, site-directed mutagenesis (R361), EMT assays, in vivo metastasis model Oncogene Medium 36991117
2023 PRMT5 symmetrically dimethylates MST2 (STK3) at arginine 461 and 467 in its SARAH domain, suppressing MST2 autophosphorylation and kinase activity by blocking MST2 homodimerization, thereby inactivating the Hippo signaling pathway in pancreatic cancer. In vitro methylation assay, kinase activity assay, homodimerization assay, site-directed mutagenesis, xenograft model with PRMT5 inhibitor GSK3326595 The EMBO journal Medium 37905571
2021 PRMT5 methylates and stabilizes KLF5 at arginine 57 (R57) in basal-like breast cancer cells; KLF5-R57me2 antagonizes GSK3β-mediated phosphorylation and subsequent Fbw7-mediated ubiquitination and degradation of KLF5, promoting breast cancer stem cell maintenance. Co-IP, in vitro methylation assay, site-directed mutagenesis (R57), ubiquitination assay, phosphorylation assay, KLF5 stability measurement Cell death and differentiation Medium 33972717
2022 PRMT5 methylates MTHFD1 at R173, enhancing its metabolic activity to generate NADPH under suspension conditions; this promotes anoikis resistance and cancer metastasis. Interaction between MTHFD1 and PRMT5 is strengthened under suspension, increasing MTHFD1 symmetric dimethylation. CRISPR metabolic screen, Co-IP, in vitro methylation assay, NADPH measurement, anoikis assay, in vivo metastasis model Oncogene Medium 35798877
2025 PRMT5 catalyzes symmetric dimethylation of GPX4 at arginine 152 (R152), preventing Cullin1-FBW7 E3 ligase binding and thereby blocking ubiquitination-mediated GPX4 degradation. PRMT5 inhibition decreases GPX4 protein levels, increasing ferroptosis inducer sensitivity. In vitro methylation assay, GPX4 half-life measurement, ubiquitination assay, site-directed mutagenesis (R152), Co-IP with Cullin1-FBW7, in vivo tumor models Nature cell biology High 40033101
2018 PRMT5 methylates DUSP14 at arginine residues 17, 38, and 45; this arginine methylation is required for TRAF2-mediated lysine ubiquitination and DUSP14 phosphatase activation, forming a sequential regulatory mechanism that inhibits TCR signaling. Proximity ligation assay, in vitro methylation assay, site-directed mutagenesis (triple mutant R17/38/45), ubiquitination assay, PRMT5 shRNA KD in T cells FASEB journal Medium 29920217
2019 PRMT5 methylates specific arginine residues preferentially within Gly-Arg-Gly (GRG) sequences; global proteomics defined the PRMT5 substrate landscape including both chromatin-bound and cytoplasmic proteins. In vitro methylation assays validated multiple novel PRMT5 substrates. SILAC with immunoenriched methyl peptides, heavy methyl SILAC validation, in vitro methylation assay, PRMT5 selective inhibitor Science signaling High 30940768
2021 PRMT5 directly interacts with EZH2; PRMT5-mediated histone marks H4R3me2s and H3R8me2s at the CDKN2B promoter reduce CpG methylation and silence CDKN2B expression. PRMT5 also enhances EZH2 binding and H3K27me3 deposition at the CDKN2B locus. Co-IP, GST pulldown, ChIP assay, bisulfite sequencing, luciferase reporter, immunofluorescence Theranostics Medium 33664859
2015 PRMT5 methylates arginine residues within the third intracellular loop of the D2 dopamine receptor, enhancing D2 receptor-mediated inhibition of cAMP signaling. In C. elegans, prmt-5-dependent methylation of DOP-3 promotes dopamine-mediated chemosensory and locomotory behaviors. In vitro methylation assay, site-directed mutagenesis of receptor arginine residues, cAMP signaling assay in HEK293T cells, C. elegans behavioral analysis Science signaling Medium 26554819
2011 PRMT5 works in concert with ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing; COPR5 is required for PRMT5 recruitment to the promoters of p21 and myogenin (MYOG) during myogenic differentiation, and COPR5-PRMT5 complex is targeted partly through interaction with the RUNX1-CBFβ complex. COPR5 siRNA silencing in C2C12 cells, ChIP for PRMT5 recruitment, in vivo muscle regeneration assay, Co-IP Cell death and differentiation Medium 22193545
2020 OXR1A physically associates with PRMT5 and directly stimulates PRMT5/MEP50-catalyzed symmetric dimethylation of histone H3R2 (H3R2me2s) as demonstrated with purified proteins. OXR1A depletion reduces H3R2me2s at the growth hormone (GH) promoter, reducing GH production in pituitary cells. Pull-down assay, proximity ligation assay, ChIP, in vitro PRMT5/MEP50 activity assay with purified OXR1A protein Cell reports Medium 32209476
2024 PRMT5 mediates FoxO1 symmetric dimethylation, which destabilizes FoxO1 and promotes its cytoplasmic retention. Loss of PRMT5 in myoblasts increases total FoxO1 and promotes cytoplasmic FoxO1 accumulation, activating autophagy and depleting lipid droplets, impairing muscle development. Muscle-specific PRMT5 KO (Myod1Cre), FoxO1 methylation and stability assays, autophagy assays, lipid droplet quantification, systemic autophagy inhibition rescue Cell reports Medium 37883229
2016 c-Myc associates with PRMT5 and its cofactor MEP50, stimulating H4R3me2s histone modification; this Myc-PRMT5-MEP50 complex activity is required for Myc target gene activation, and PRMT5 inhibition impairs Myc-dependent transcription activation. Co-IP, confocal co-localization, H4R3me2s ChIP, PRMT5 activity inhibition experiments in glioblastoma and HEK293T cells Scientific reports Medium 26563484
2021 PRMT5 regulates ATF4 pre-mRNA splicing; PRMT5 inhibition results in expression of unstable, intron-retaining ATF4 mRNA detained in the nucleus, reducing cytoplasmic ATF4 protein and downregulating ATF4 target genes, increasing oxidative stress and cellular senescence. RNA-seq splicing analysis, nuclear/cytoplasmic fractionation, PRMT5 inhibitor treatment in AML cells Redox biology Medium 35305370
2023 PRMT5 selectively methylates KEAP1, downregulating NRF2 and its downstream ferroptosis-regulating targets; in TNBC cells with high ferrous concentration, PRMT5 inhibits the NRF2/HMOX1 pathway and slows ferrous import, promoting ferroptosis resistance. Biochemical assays, PRMT5 KD/inhibition, NRF2 target gene expression, iron metabolism measurement in TNBC vs non-TNBC cells Journal for immunotherapy of cancer Low 37380368
2024 PRMT5 is recruited by TGF-β-activated Smad3 to the α-SMA promoter in cardiac fibroblasts, increasing H3R2 symmetric dimethylation; this mark is then read by the WDR5/MLL1 complex, increasing H3K4 trimethylation and driving fibrotic gene transcription. PRMT5 deficiency reduces pressure overload-induced cardiac fibrosis. Fibroblast-specific PRMT5 KO, ChIP for PRMT5/Smad3 complex and histone marks, Smad3 siRNA rescue, pharmacological inhibition (EPZ015666), in vivo pressure overload model Nature communications Medium 38503742
2023 PRMT5 catalyzes symmetric dimethylation of ALKBH5 at R316, enhancing TRIM28-mediated ALKBH5 ubiquitination and degradation; reduced ALKBH5 decreases m6A demethylation on CD276 mRNA, stabilizing CD276 expression and promoting CRC immune evasion. Co-IP, in vitro methylation assay, ubiquitination assay, m6A measurement, PRMT5 inhibitor (GSK3326595) treatment, in vivo CRC model Research (Washington, D.C.) Medium 39781264
2022 PRMT5 methylates Mxi1, promoting binding of the β-TrCP ligase to Mxi1, facilitating Mxi1 ubiquitination and degradation, thereby conferring radioresistance in non-small cell lung cancer. Co-IP, in vitro methylation assay, ubiquitination assay, site-directed mutagenesis, radiosensitivity assays, in vivo xenograft Cancer letters Medium 35149174
2019 In zebrafish, Prmt5 catalyzes arginine methylation of germline-specific proteins Zili (PIWI) and Vasa, as well as histones H3R8 and H4R3, in gonads. Loss of prmt5 downregulates PIWI pathway proteins and disrupts germ cell development, meiosis, and gonadal differentiation. prmt5 null zebrafish, methylation assays for Zili/Vasa/histones, germ cell apoptosis assays, gene expression analysis Development Medium 31533925
2019 PRMT5 is required for hematopoietic stem cell quiescence and viability by modulating splicing of DNA repair genes; PRMT5 depletion causes exon skipping and intron retention events across multiple DNA repair pathways (including interstrand crosslink repair and homologous recombination), leading to DNA damage, p53 activation, and HSC exhaustion. Conditional PRMT5 KO in HSCs, RNA-seq splicing analysis, γH2AX foci quantification, p53 depletion rescue, HSC flow cytometry Cell reports High 30811983
2023 PRMT5 promotes ENO1 dimerization and glycolysis in ovarian cancer by symmetrically dimethylating ENO1 at arginine 9 (R9), promoting active ENO1 dimer formation. High glucose signaling increases PRMT5-mediated ENO1 methylation. In vitro methylation assay, ENO1 dimerization assay, glycolysis flux measurement, PRMT5 KD/inhibition, site-directed mutagenesis MedComm Medium 36999124
2023 PRMT5 methylates G3BP2 at R468, enhancing G3BP2 binding to deubiquitinase USP7, which deubiquitinates and stabilizes G3BP2; stabilized G3BP2 activates ACLY to stimulate de novo lipogenesis and tumorigenesis in HNSC. Co-IP, in vitro methylation assay, ubiquitination/deubiquitination assay, ACLY activity measurement, PRMT5 inhibitor treatment Cell death & disease Medium 36878903

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science (New York, N.Y.) 519 26912360
2016 Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science (New York, N.Y.) 447 26912361
2015 The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cellular and molecular life sciences : CMLS 413 25662273
2016 MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell reports 352 27068473
2011 Versatility of PRMT5-induced methylation in growth control and development. Trends in biochemical sciences 234 21975038
2020 PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Science translational medicine 194 32641491
2021 MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer cell 179 33450196
2020 PRMT5 function and targeting in cancer. Cell stress 175 32743345
2009 PRMT5 is required for cell-cycle progression and p53 tumor suppressor function. Nucleic acids research 171 19528079
2023 MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. Cancer discovery 157 37552839
2019 Arginine methylation of the DDX5 helicase RGG/RG motif by PRMT5 regulates resolution of RNA:DNA hybrids. The EMBO journal 146 31267554
2016 Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. The Journal of clinical investigation 144 27643437
2021 PRMT5 inhibition disrupts splicing and stemness in glioblastoma. Nature communications 137 33579912
2011 Arabidopsis floral initiator SKB1 confers high salt tolerance by regulating transcription and pre-mRNA splicing through altering histone H4R3 and small nuclear ribonucleoprotein LSM4 methylation. The Plant cell 137 21258002
2019 Proteomics profiling of arginine methylation defines PRMT5 substrate specificity. Science signaling 136 30940768
2014 PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos. Molecular cell 118 25457166
2016 PRMT5-PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells. Oncogene 112 27292259
2022 Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review. Journal of immunotherapy and precision oncology 103 36034581
2019 Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proceedings of the National Academy of Sciences of the United States of America 100 31439820
2019 PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis. Cell communication and signaling : CCS 93 30922330
2018 Protein arginine methyltransferase 5 (PRMT5) dysregulation in cancer. Oncotarget 92 30613353
2022 PRMT5 activates AKT via methylation to promote tumor metastasis. Nature communications 84 35803962
2018 Protein Arginine Methyltransferase 5 (PRMT5) as an Anticancer Target and Its Inhibitor Discovery. Journal of medicinal chemistry 83 29870258
2015 Discovery of a Dual PRMT5-PRMT7 Inhibitor. ACS medicinal chemistry letters 81 25893041
2019 PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells. Cell reports 79 30811983
2020 Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders. Journal of medicinal chemistry 78 32787082
2021 Molecular basis for substrate recruitment to the PRMT5 methylosome. Molecular cell 77 34358446
2019 PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic acids research 77 30916320
2021 PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis. Nature communications 75 34103528
2023 STC2 activates PRMT5 to induce radioresistance through DNA damage repair and ferroptosis pathways in esophageal squamous cell carcinoma. Redox biology 72 36764215
2019 PRMT5 is essential for B cell development and germinal center dynamics. Nature communications 71 30604754
2019 UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells. Nature communications 71 31624244
2021 Arginine methyltransferase PRMT5 negatively regulates cGAS-mediated antiviral immune response. Science advances 69 33762328
2019 PRMT5 in gene regulation and hematologic malignancies. Genes & diseases 68 32042864
2014 Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. Human pathology 67 24775604
2021 PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression. Theranostics 66 33664859
2023 PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis. Journal for immunotherapy of cancer 65 37380368
1996 The highly conserved skb1 gene encodes a protein that interacts with Shk1, a fission yeast Ste20/PAK homolog. Proceedings of the National Academy of Sciences of the United States of America 64 8943016
2023 PRMT5 methylating SMAD4 activates TGF-β signaling and promotes colorectal cancer metastasis. Oncogene 63 36991117
2021 SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance. Molecular cancer therapeutics 61 34737197
2023 Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies. Journal of medicinal chemistry 60 37366223
2018 Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. Journal of cellular and molecular medicine 60 30461193
2017 PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 57 28087667
2020 PRMT5 promotes DNA repair through methylation of 53BP1 and is regulated by Src-mediated phosphorylation. Communications biology 56 32759981
2021 The Structure and Functions of PRMT5 in Human Diseases. Life (Basel, Switzerland) 53 34685445
2021 Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition. Cell death and differentiation 52 33953349
2021 Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer. Cell death and differentiation 52 33972717
2019 NAA40 contributes to colorectal cancer growth by controlling PRMT5 expression. Cell death & disease 52 30858358
2021 PRMT5: a putative oncogene and therapeutic target in prostate cancer. Cancer gene therapy 42 33854218
2020 PRMT5/Wnt4 axis promotes lymph-node metastasis and proliferation of laryngeal carcinoma. Cell death & disease 41 33060569
2015 Prmt5 is required for germ cell survival during spermatogenesis in mice. Scientific reports 41 26072710
2022 PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer. Frontiers in immunology 40 35111150
2019 Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors. Bioorganic & medicinal chemistry letters 40 30956011
2022 The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression. Molecular cancer 39 35624451
2018 LKB1 regulates PRMT5 activity in breast cancer. International journal of cancer 39 30289978
2020 PRMT5 Is Required for T Cell Survival and Proliferation by Maintaining Cytokine Signaling. Frontiers in immunology 38 32328070
2015 Myc and Omomyc functionally associate with the Protein Arginine Methyltransferase 5 (PRMT5) in glioblastoma cells. Scientific reports 38 26563484
2014 The Sm protein methyltransferase PRMT5 is not required for primordial germ cell specification in mice. The EMBO journal 38 25519955
2001 The highly conserved protein methyltransferase, Skb1, is a mediator of hyperosmotic stress response in the fission yeast Schizosaccharomyces pombe. The Journal of biological chemistry 36 11278267
2022 Medicinal chemistry strategies targeting PRMT5 for cancer therapy. European journal of medicinal chemistry 34 36274274
2013 Arabidopsis histone methylase CAU1/PRMT5/SKB1 acts as an epigenetic suppressor of the calcium signaling gene CAS to mediate stomatal closure in response to extracellular calcium. The Plant cell 34 23943859
2021 PRMT5 regulates colorectal cancer cell growth and EMT via EGFR/Akt/GSK3β signaling cascades. Aging 33 33495409
2017 The Structure and Function of the PRMT5:MEP50 Complex. Sub-cellular biochemistry 32 28271477
2020 Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5). ACS medicinal chemistry letters 31 32944135
2022 PRMT5 regulates ATF4 transcript splicing and oxidative stress response. Redox biology 30 35305370
2022 Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis. Oncogene 30 35798877
2022 Arginine methyltransferase PRMT5 methylates and destabilizes Mxi1 to confer radioresistance in non-small cell lung cancer. Cancer letters 29 35149174
2019 Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations. Chemical & pharmaceutical bulletin 29 30930442
2025 PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer. Nature cell biology 26 40033101
2023 Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation. Nature communications 26 36609611
2022 Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype. JCI insight 26 35439169
2019 Zebrafish prmt5 arginine methyltransferase is essential for germ cell development. Development (Cambridge, England) 26 31533925
2023 PRMT5 promotes ovarian cancer growth through enhancing Warburg effect by methylating ENO1. MedComm 25 36999124
2023 PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma. Blood 25 37267517
2023 MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression. The EMBO journal 25 37905571
2022 Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer. Journal of experimental & clinical cancer research : CR 25 36199122
2020 OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation. Cell reports 25 32209476
2020 PRMT5 inhibition attenuates cartilage degradation by reducing MAPK and NF-κB signaling. Arthritis research & therapy 24 32887644
2023 PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors. Cell reports 23 37883229
2023 Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. The Journal of biological chemistry 23 38000655
2015 The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling. Science signaling 23 26554819
2018 Induction of DUSP14 ubiquitination by PRMT5-mediated arginine methylation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 29920217
2024 Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice. Nature communications 21 38503742
2011 The histone- and PRMT5-associated protein COPR5 is required for myogenic differentiation. Cell death and differentiation 21 22193545
2024 Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer. Journal of experimental & clinical cancer research : CR 20 39614393
2023 The Role of PRMT5 in Immuno-Oncology. Genes 20 36980950
2023 A patent review of PRMT5 inhibitors to treat cancer (2018 - present). Expert opinion on therapeutic patents 20 37072380
2022 Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors. Journal of medicinal chemistry 20 36378254
2021 Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel. Proceedings of the National Academy of Sciences of the United States of America 20 34408017
2016 The arginine methyltransferase PRMT5 regulates CIITA-dependent MHC II transcription. Biochimica et biophysica acta 20 26972221
2023 USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC. Cell death & disease 18 36878903
2020 EPZ015666, a selective protein arginine methyltransferase 5 (PRMT5) inhibitor with an antitumour effect in retinoblastoma. Experimental eye research 18 33035554
2013 Histone H4R3 methylation catalyzed by SKB1/PRMT5 is required for maintaining shoot apical meristem. PloS one 18 24349476
2022 PRMT5 Interacting Partners and Substrates in Oligodendrocyte Lineage Cells. Frontiers in cellular neuroscience 17 35370564
2024 Identification of PRMT5 as a therapeutic target in cholangiocarcinoma. Gut 16 39266051
2025 PRMT5-Mediated ALKBH5 Methylation Promotes Colorectal Cancer Immune Evasion via Increasing CD276 Expression. Research (Washington, D.C.) 15 39781264
2024 Role of PRMT1 and PRMT5 in Breast Cancer. International journal of molecular sciences 15 39201539
2023 PRMT5 facilitates angiogenesis and EMT via HIF-1α/VEGFR/Akt signaling axis in lung cancer. Aging 15 37400960
2023 Protein arginine methyltransferases PRMT1, PRMT4/CARM1 and PRMT5 have distinct functions in control of osteoblast differentiation. Bone reports 15 37593409
2024 Medicinal chemistry insights into PRMT5 inhibitors. Bioorganic chemistry 14 39378783