{"gene":"WDR77","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2012,"finding":"Crystal structure of the human PRMT5:MEP50 hetero-octameric complex (4 PRMT5 + 4 MEP50) bound to an SAM analog and histone H4 peptide substrate revealed that MEP50's seven-bladed β-propeller interacts with the N-terminal domain of PRMT5, delineating structural elements of substrate recognition.","method":"X-ray crystallography with bound cofactor analog and peptide substrate","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with bound substrate and cofactor, defining hetero-octameric architecture and MEP50-PRMT5 interface","pmids":["23071334"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of the human PRMT5:MEP50 complex at 3.7 Å confirmed the 450 kDa hetero-octameric assembly with D2 internal symmetry; MEP50 subunits are arranged peripherally in complex with the PRMT5 N-terminal domain, consistent with the crystal structure.","method":"Single-particle cryo-electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent cryo-EM structure replicating and extending the crystal structure finding","pmids":["29518110"],"is_preprint":false},{"year":2015,"finding":"MEP50 is required for efficient histone methylation by PRMT5; the cross-dimer MEP50 is paired with its cognate PRMT5 to promote histone methylation. Mutation of a conserved arginine (Arg-42) on the MEP50 insertion loop increased the histone substrate Km, impairing PRMT5-MEP50 enzymatic efficiency. Neither full-length human PRMT5 nor the Xenopus PRMT5 catalytic domain has appreciable protein methyltransferase activity alone. Histones H4 and H3 bind PRMT5-MEP50 via histone fold interactions, and nucleosomes are not substrates.","method":"In vitro methylation assays including continuous kinetic assay, site-directed mutagenesis of MEP50 Arg-42, competition experiments, high-density histone peptide array interaction studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with mutagenesis and multiple orthogonal substrate-binding assays; establishes MEP50 as obligate activator positioning substrate","pmids":["25713080"],"is_preprint":false},{"year":2011,"finding":"Xenopus Prmt5-Mep50 complex isolated from eggs specifically methylates pre-deposition histones H2A/H2A.X-F and H4, and the histone chaperone nucleoplasmin at Arg-187 (mono- and symmetric dimethylation). Nucleoplasmin modulates Prmt5-Mep50 activity directed toward histones, consistent with a regulatory role.","method":"Biochemical complex isolation, mass spectrometry identification of methylation sites, in vitro methylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted complex, MS-identified methylation sites, in vitro activity assays in single lab","pmids":["22009756"],"is_preprint":false},{"year":2016,"finding":"PRMT5-MEP50 catalyzes histone mono- and dimethylation (H3R2me1 and H4R3me2s) at chromatin of metastasis suppressor and EMT genes in response to TGFβ; H3R2me1 recruits WDR5 for concomitant H3K4 methylation and transcriptional activation, while H4R3me2s suppresses transcription at distinct loci.","method":"ChIP-seq, RNA-seq, knockdown of PRMT5 and MEP50, chromatin immunoprecipitation for histone marks","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP and knockdown with orthogonal transcriptomic readout; establishes mechanistic pathway linking PRMT5-MEP50 activity to TGFβ-driven transcriptional outcomes","pmids":["27270440"],"is_preprint":false},{"year":2017,"finding":"Nuclear PRMT5/WDR77 complex symmetrically dimethylates ZNF326 at Arg-175 (R175me2s), a modification lost upon PRMT5 or WDR77 depletion; loss of either subunit causes defects in alternative splicing including inclusion of A-T rich exons in target genes, phenocopying ZNF326 loss.","method":"Mass spectrometry identification of ZNF326 as substrate, Co-IP, methylation assays, RNA-seq splicing analysis, knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification of substrate and modification site, biochemical validation, orthogonal splicing readout","pmids":["28977470"],"is_preprint":false},{"year":2018,"finding":"SIRT7 directly deacetylates WDR77 at Lys-3 and Lys-243; this deacetylation reduces WDR77's interaction with PRMT5, suppresses WDR77/PRMT5 transmethylase activity and H4R3me2 levels, and reduces colon cancer cell proliferation and migration. WDR77-2KR (K3R/K243R) variant showed reduced PRMT5 interaction and activity compared to WT.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K3R, K243R), H4R3me2 methylation assay, KO rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deacetylation, mutagenesis rescue, and KO cellular phenotype; multiple orthogonal methods in single lab","pmids":["30282801"],"is_preprint":false},{"year":2019,"finding":"MEP50/PRMT5 complex associates with GLI1 and methylates it; methylated GLI1 loses its ability to bind ubiquitin ligase ITCH/NUMB, resulting in nuclear accumulation and activation of GLI1 in the Hedgehog signaling pathway. HH signals enhance MEP50/PRMT5-GLI1 association.","method":"Co-immunoprecipitation, methylation assays, nuclear/cytoplasmic fractionation, ubiquitination assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and methylation demonstrated in cells, functional link to ubiquitination and nuclear accumulation established, single lab","pmids":["30675521"],"is_preprint":false},{"year":2018,"finding":"PHF1 N-terminal PHD finger recognizes H4R3me2s catalyzed by PRMT5-WDR77; PHF1, PRMT5-WDR77, and CRL4B complex (DDB1/CUL4B) reciprocally interact and collaborate as a functional unit to regulate target genes including E-cadherin and FBXW7.","method":"Co-IP, histone peptide binding assays, ChIP-seq, genome-wide target analysis, knockdown/overexpression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and peptide binding for reader identification, ChIP-seq for targets; single lab","pmids":["29846670"],"is_preprint":false},{"year":2021,"finding":"HBx drives the cellular DDB1-containing E3 ubiquitin ligase to degrade WDR77 by recruiting WDR77 to the DDB1 complex; WDR77 degradation disables PRMT5-triggered H4R3me2s on cccDNA minichromosome, releasing transcriptional repression and promoting HBV replication.","method":"Co-IP, Western blot, ChIP assay, Southern/Northern blot, immunofluorescence in PHHs, HepG2-NTCP cells, and human liver-chimeric mice","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrated DDB1-WDR77 interaction, ChIP showed H4R3me2s on cccDNA, in vivo liver-chimeric mouse model; single lab","pmids":["34373747"],"is_preprint":false},{"year":2023,"finding":"WDR77 binds to the proline-rich region of MAVS through its WD2-WD3-WD4 domain and inhibits the formation of prion-like MAVS filaments in vitro; upon virus infection, WDR77 is recruited to MAVS to prevent prion-like aggregation and downregulate RIG-I-MAVS signaling. Myeloid-specific Wdr77-deficient mice showed enhanced antiviral responses to negative-strand RNA viruses.","method":"Co-IP (MAVS-WDR77 interaction), in vitro filament formation assay with recombinant proteins, domain mapping, myeloid-specific KO mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstituted filament inhibition assay, domain-mapping, conditional KO mouse; multiple orthogonal methods","pmids":["37563140"],"is_preprint":false},{"year":2023,"finding":"PRMT5/WDR77 complex catalyzes methylation of HEV ORF1 replicase at Arg-458 (R458), impairing its replicase activity; virus bearing R458K mutation in ORF1 relieves PRMT5/WDR77-dependent restriction of HEV replication.","method":"SILAC/mass spectrometry identification, HEV replicon system, ORF1 methylation assay, R458K mutant virus rescue experiment","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of methylation site, mutant virus rescue confirms functional relevance; single lab","pmids":["37276230"],"is_preprint":false},{"year":2023,"finding":"The PRMT5/MEP50/pICln methylosome methylates two arginine residues in the N-terminal region of Lsm11 and an N-terminal arginine in SmE (a modification distinct from spliceosomal snRNP biogenesis); the Lsm10-Lsm11 heterodimer interaction with the methylosome is mediated by PRMT5.","method":"Biochemical interaction assays, cryo-EM structural analysis of Lsm10/Lsm11-methylosome complex, in vitro methylation assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus in vitro methylation assays establishing interaction and substrate specificity; single lab","pmids":["37562960"],"is_preprint":false},{"year":2021,"finding":"WDR77 germ-line missense mutation R198H impairs its interaction with PRMT5, and a splice-site mutation causes exon 6 skipping leading to markedly decreased mutant mRNA and obviously reduced H4R3me2 levels in mutation carriers.","method":"Whole-exome sequencing, Co-IP of R198H mutant vs WT for PRMT5 interaction, H4R3me2 Western blot in patient-derived tissue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived tissue validation with Co-IP interaction assay and histone mark readout; single study","pmids":["34326253"],"is_preprint":false},{"year":2011,"finding":"p44/WDR77 contains functional nuclear localization signals (NLS) and nuclear exclusion signals (NES); site-directed mutagenesis of critical NLS residues abolished nuclear localization and transcriptional coactivator activity for AR. p44/WDR77 localizes cytoplasmically during prostate proliferation and translocates to the nucleus during differentiation.","method":"Subcellular localization assays spanning full ORF, NLS/NES mutagenesis, AR transcriptional reporter assays, MALDI-TOF/TOF mass spectrometry of NLS/NES-associated proteins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis linked to functional transcriptional readout and localization; single lab with multiple methods","pmids":["21789256"],"is_preprint":false},{"year":2012,"finding":"Cytoplasmic p44/WDR77 is essential for proliferation of prostate epithelial cells, while nuclear p44/WDR77 is required for cell differentiation and prostate-specific protein secretion; loss of p44/WDR77 leads to cell growth arrest partially through the p21-Rb signaling pathway.","method":"Conditional KO mouse model, re-expression rescue experiments, subcellular fractionation, cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse and re-expression with defined cellular phenotypes and pathway readout; single lab","pmids":["23145110","22665061"],"is_preprint":false},{"year":2012,"finding":"Deletion of p44/WDR77 gene causes premature death with dramatic astrogliosis; loss of p44/WDR77 in astrocytes leads to growth arrest and astrocyte activation associated with upregulation of p21(Cip1) expression and NF-κB activation. Silencing p21(Cip1) or NF-κB p65 with shRNA abolished astrocyte activation and rescued growth inhibition.","method":"Gene knockout mouse model, shRNA knockdown epistasis experiment, Western blot, GFAP immunostaining","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KO + shRNA rescue) in mouse model placing WDR77 upstream of p21/NF-κB in astrocyte activation; single lab","pmids":["22751923"],"is_preprint":false},{"year":2010,"finding":"p44/WDR77-null mouse prostates showed smaller glands with fewer branches, less differentiation, hyperproliferation, and altered expression of androgen-regulated genes, indicating that WDR77 plays a role in prostate growth and differentiation by modulating AR-target gene expression.","method":"Conditional KO mouse model, histology, gene expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined morphological and molecular phenotype; single lab","pmids":["20519372"],"is_preprint":false},{"year":2006,"finding":"SUZ12 interacts with MEP50 both in vitro and in vivo; MEP50 binds histone H2A selectively among core histones and mediates transcriptional repression by PRMT5.","method":"Co-immunoprecipitation (in vivo), in vitro binding assays, histone binding specificity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus in vitro binding; two orthogonal methods but single lab","pmids":["16712789"],"is_preprint":false},{"year":2003,"finding":"MEP50 was identified as a novel FCP1-interacting protein by mass spectrometry of affinity-purified FCP1 complexes; FCP1 specifically interacts with components of spliceosomal U snRNPs, suggesting a role in linking transcription elongation with splicing.","method":"Affinity purification of epitope-tagged FCP1, mass spectrometry identification","journal":"Nucleic acids research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single affinity-purification/MS identification, no mechanistic follow-up on MEP50 specifically","pmids":["12560496"],"is_preprint":false},{"year":2017,"finding":"The structure of the PRMT5:MEP50 hetero-octameric complex provides a basis for understanding how MEP50's β-propeller positions substrate arginines toward the PRMT5 catalytic site; MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel defines a protein-protein interaction interface targetable by small molecules.","method":"Structural analysis review; small-molecule virtual screen + molecular docking validating the PPI interface","journal":"Sub-cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural interpretation review supported by docking; mechanistic detail about W54 later validated experimentally in PMID 36206451","pmids":["28271477"],"is_preprint":false},{"year":2022,"finding":"Compound 17, a small-molecule PRMT5:MEP50 PPI inhibitor, disrupts MEP50 W54 burial into the PRMT5 TIM barrel hydrophobic pocket, selectively inhibiting PRMT5:MEP50 substrate methylation (IC50 <500 nM in cancer cells) and confirming the MEP50-PRMT5 interface as a druggable site.","method":"Virtual screening, molecular docking, in vitro methylation inhibition assays, RNA-seq","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro activity assay with selective inhibition, docking-guided mechanism; single lab","pmids":["36206451"],"is_preprint":false},{"year":2021,"finding":"The interface between the TIM barrel of PRMT5 and adaptor proteins pICln, RioK1, and COPR5 involves the consensus amino acid sequence GQF[D/E]DA[E/D]; protein crystallography of the RioK1-derived peptide revealed a novel PPI site on PRMT5.","method":"Peptide truncation and mutation studies, protein crystallography","journal":"Chembiochem : a European journal of chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of peptide at novel PPI site, validated by mutagenesis; single lab","pmids":["33624332"],"is_preprint":false},{"year":2024,"finding":"TBL2 acts as a scaffolding protein that promotes PRMT5 and WDR77 interaction; this enhances PRMT5 methyltransferase activity, leading to increased AKT phosphorylation in breast cancer cells.","method":"Proteomic analysis, co-immunoprecipitation, methyltransferase activity assay, in vivo and in vitro proliferation assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and methyltransferase assay with in vivo validation; single lab","pmids":["39499734"],"is_preprint":false},{"year":2016,"finding":"WDR77 was identified as a protein interacting with TSC22D2 by yeast two-hybrid screening; the interaction was confirmed by co-immunoprecipitation and co-localization by immunofluorescence.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirmation of Y2H hit; no mechanistic follow-up","pmids":["27337956"],"is_preprint":false},{"year":2013,"finding":"The N-terminal region of p44/WDR77 (not the C-terminal WD40 domain) mediates interaction with the N-terminus of AR and full-length Smad1, forming a ternary AR-p44-Smad1 complex; both N- and C-terminal domains are needed for maximum AR transcriptional activation, while the central portion is required for nuclear p44-mediated prostate cancer growth inhibition.","method":"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assays, deletion mutagenesis, cell proliferation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP with luciferase functional readout and domain mutagenesis; single lab","pmids":["23734213"],"is_preprint":false},{"year":2014,"finding":"Silencing p44/WDR77 increased cellular sensitivity to TGFβ signaling, inducing Smad2/3 phosphorylation, TGFβ-mediated transcription, and TGFβ2 and TβRII expression, suggesting WDR77 downregulates TGFβ ligand and receptor expression to restrict TGFβ pathway activity in proliferating cells.","method":"shRNA knockdown, phospho-Smad Western blot, TGFβ-responsive reporter assay, qPCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple molecular readouts; single lab, single study","pmids":["24944016"],"is_preprint":false},{"year":2025,"finding":"RNF187 interacts with WDR77 and catalyzes lysine 48-linked polyubiquitination of WDR77 at K118, mediating its proteasomal degradation. Decreased WDR77 reduces H4R3me2s by PRMT5, relieving transcriptional repression of EGR1 and thereby promoting human spermatogonial stem cell proliferation and migration.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination site mapping (K118), proteasome inhibitor experiments, H4R3me2s Western blot, EGR1 reporter","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS substrate identification, and site-specific ubiquitination with functional downstream readout; single lab","pmids":["40197797"],"is_preprint":false},{"year":2025,"finding":"WDR77 directly interacts with AR and when this interaction is disrupted, AR-WDR77 complex formation is prevented, reducing AR DNA-binding, AR-dependent gene expression, and cell proliferation; AR and WDR77 cistromes overlap considerably at AR-regulated genes associated with aggressive prostate cancer.","method":"Co-immunoprecipitation, ChIP-seq (AR and WDR77 cistromes), disruption of WDR77-AR interaction, organoid models, patient-derived xenograft growth assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and functional rescue in organoids; single lab","pmids":["40934084"],"is_preprint":false},{"year":2022,"finding":"MafB, β-catenin, and WDR77 interact directly with each other and share similar genomic binding profiles; their common target sites are enriched just downstream of transcription initiation sites near paused RNA polymerase and the +1 nucleosome, and occupancy correlates with transcriptional activity.","method":"Co-immunoprecipitation, ChIP-seq for all three factors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and genome-wide ChIP-seq demonstrating co-occupancy; single lab","pmids":["35482762"],"is_preprint":false},{"year":2025,"finding":"PRMT5 is prone to aggregation when expressed at supra-stoichiometric levels relative to its obligate partner MEP50/WDR77; co-increased expression of PRMT5 and MEP50 mitigates protein aggregation induced by chromosomal instability, rendering cancer cells less sensitive to proteasome inhibitors.","method":"Protein aggregation assays, co-expression studies, proteasome inhibitor sensitivity assays in CIN models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, aggregation assay without full mechanistic dissection","pmids":["bio_10.1101_2025.09.12.675799"],"is_preprint":true},{"year":2025,"finding":"PRMT5 acts as an RNA-binding protein in a methyltransferase activity-independent manner and promotes PDCD1 (PD-1) mRNA decay together with WDR77 and Argonaute2; the PRMT5/WDR77 complex binds a conserved AU-rich element in the PDCD1 3' UTR. IFN/STAT1 signaling transcriptionally activates PRMT5 and WDR77, enhancing their binding to PDCD1 mRNA. Conditional KO of WDR77 in T cells disrupts T cell effector function and sensitizes tumors to anti-PD-1 therapy.","method":"RNA immunoprecipitation, RNA decay assay, conditional KO mouse model, 3' UTR reporter assay, Co-IP with Argonaute2","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, RNA decay assay, conditional KO with immunological phenotype; single lab but multiple orthogonal methods","pmids":["41623183"],"is_preprint":false},{"year":2025,"finding":"C6orf223 forms dimers through disulfide bonds; its N-terminal arginine-enriched region binds to the C-terminal negatively charged groove of PRMT5, stabilizing the PRMT5-MEP50 multiprotein complex and enhancing PRMT5 methyltransferase activity.","method":"Co-immunoprecipitation, domain-mapping, methyltransferase activity assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and activity assay; single lab","pmids":["41090362"],"is_preprint":false}],"current_model":"WDR77/MEP50 is an obligate WD40 β-propeller cofactor of PRMT5 that forms a ~450 kDa hetero-octameric complex (four PRMT5 : four MEP50) in which MEP50's β-propeller contacts the PRMT5 N-terminal domain and positions protein substrates (histones H2A, H4, H3, nucleoplasmin, ZNF326, GLI1, HEV ORF1, Lsm11, SmE) toward the PRMT5 catalytic site for symmetric arginine dimethylation; PRMT5 alone has negligible activity, making MEP50 an obligate activator. WDR77 also functions as a MAVS-binding suppressor of prion-like MAVS aggregation to limit innate antiviral signaling, and as an mRNA-stability co-factor with PRMT5 to promote PDCD1 decay in T cells. Its activity is regulated post-translationally: SIRT7 deacetylates WDR77 at K3/K243 to weaken PRMT5 binding and reduce methyltransferase output, while RNF187 ubiquitinates WDR77 at K118 for proteasomal degradation and HBx co-opts DDB1 E3 ligase to degrade WDR77. Subcellular localization—controlled by NLS/NES sequences—dictates function: cytoplasmic WDR77 drives proliferation while nuclear WDR77 supports differentiation and AR/ER co-activation."},"narrative":{"mechanistic_narrative":"WDR77 (MEP50/p44) is an obligate WD40 β-propeller cofactor of the protein arginine methyltransferase PRMT5, assembling into a ~450 kDa hetero-octameric complex of four PRMT5 and four MEP50 subunits in which MEP50's seven-bladed β-propeller contacts the PRMT5 N-terminal domain and positions protein substrates toward the catalytic site [PMID:23071334, PMID:29518110]. PRMT5 has negligible methyltransferase activity alone, and MEP50 acts as an obligate activator: a conserved Arg-42 on the MEP50 insertion loop lowers the substrate Km, and the W54 residue buried in the PRMT5 TIM-barrel pocket defines the activating interface [PMID:25713080, PMID:28271477]. Through this complex WDR77 directs symmetric arginine dimethylation of histones (H2A, H4R3me2s, H3R2me1) and a broad set of non-histone substrates including nucleoplasmin, ZNF326, GLI1, the HEV ORF1 replicase, and Lsm11/SmE, thereby shaping chromatin marks, alternative splicing, Hedgehog signaling, and antiviral restriction [PMID:22009756, PMID:27270440, PMID:28977470, PMID:30675521, PMID:37276230, PMID:37562960]. The H4R3me2s mark deposited by PRMT5-WDR77 is read by the PHF1 PHD finger in concert with the CRL4B complex to repress target genes, and its loss de-represses transcription [PMID:29846670]. WDR77 activity is tuned post-translationally: SIRT7 deacetylates WDR77 at K3/K243 to weaken PRMT5 binding, RNF187 ubiquitinates WDR77 at K118 (K48-linked) for proteasomal degradation, and the scaffold TBL2 and adaptor C6orf223 enhance PRMT5-WDR77 assembly and activity [PMID:30282801, PMID:40197797, PMID:39499734, PMID:41090362]. Independent of methyltransferase function, WDR77 binds the proline-rich region of MAVS via its WD2-WD3-WD4 module to suppress prion-like MAVS aggregation and dampen RIG-I-MAVS antiviral signaling, and partners with PRMT5 and Argonaute2 as an RNA-binding complex that drives PDCD1 (PD-1) mRNA decay in T cells [PMID:37563140, PMID:41623183]. Subcellular localization governed by NLS/NES sequences partitions WDR77 function—cytoplasmic WDR77 drives proliferation while nuclear WDR77 supports differentiation and acts as an androgen receptor coactivator [PMID:21789256, PMID:23734213, PMID:40934084]. A germline WDR77 R198H missense mutation impairs PRMT5 binding and reduces cellular H4R3me2, linking WDR77 dysfunction to human disease [PMID:34326253].","teleology":[{"year":2006,"claim":"Before its structural role was known, MEP50 was placed within PRMT5-dependent transcriptional repression, establishing it as a histone-binding partner of the methyltransferase.","evidence":"Co-IP and in vitro histone-binding assays showing SUZ12 and selective H2A binding","pmids":["16712789"],"confidence":"Medium","gaps":["No structural basis for histone selectivity","Mechanism of repression not resolved at this stage"]},{"year":2011,"claim":"The first reconstituted activity defined PRMT5-MEP50 substrate scope, showing the complex methylates pre-deposition histones and the chaperone nucleoplasmin, and that localization signals partition WDR77 function between proliferation and differentiation.","evidence":"Xenopus complex isolation with MS site mapping and in vitro methylation; NLS/NES mutagenesis with AR reporter assays","pmids":["22009756","21789256"],"confidence":"Medium","gaps":["Did not establish atomic architecture of the complex","Determinants of nuclear vs cytoplasmic partitioning incompletely mapped"]},{"year":2012,"claim":"Crystallography solved the hetero-octameric architecture and revealed how MEP50's β-propeller engages the PRMT5 N-terminal domain to recognize substrate, answering how the cofactor enables catalysis.","evidence":"X-ray structure of human PRMT5:MEP50 with SAM analog and H4 peptide","pmids":["23071334"],"confidence":"High","gaps":["Did not quantify the kinetic contribution of MEP50 residues","Non-histone substrate positioning not addressed"]},{"year":2012,"claim":"In vivo knockout work established WDR77 as a regulator of proliferation versus differentiation, placing it upstream of the p21/Rb and NF-κB axes in prostate and astrocyte contexts.","evidence":"Conditional and germline KO mouse models, shRNA epistasis, subcellular fractionation, cell cycle analysis","pmids":["23145110","22665061","22751923","20519372"],"confidence":"Medium","gaps":["Molecular link between localization and p21/NF-κB output unresolved","Whether phenotypes depend on PRMT5 catalysis not dissected"]},{"year":2015,"claim":"Reconstitution with mutagenesis proved MEP50 is an obligate activator that positions substrate, pinpointing Arg-42 as a determinant of the substrate Km and showing PRMT5 alone is inactive.","evidence":"Kinetic in vitro methylation, MEP50 Arg-42 mutagenesis, histone peptide arrays","pmids":["25713080"],"confidence":"High","gaps":["Nucleosomes are not substrates—physiological substrate presentation unresolved","Did not address non-histone substrate kinetics"]},{"year":2016,"claim":"Chromatin-level studies connected PRMT5-MEP50 catalysis to opposing transcriptional outcomes, with H3R2me1 recruiting WDR5 for activation and H4R3me2s mediating repression downstream of TGFβ.","evidence":"ChIP-seq, RNA-seq, PRMT5/MEP50 knockdown; separate knockdown TGFβ-sensitivity assays","pmids":["27270440","24944016"],"confidence":"Medium","gaps":["Locus-specific determinants of activation vs repression unclear","Recruitment of the complex to specific genes not defined"]},{"year":2017,"claim":"Substrate scope was extended beyond histones, with ZNF326 methylation at R175 linking WDR77 to alternative splicing fidelity.","evidence":"MS substrate identification, Co-IP, methylation and RNA-seq splicing analysis with knockdown","pmids":["28977470"],"confidence":"High","gaps":["How methylation alters ZNF326 function mechanistically not resolved","Breadth of splicing targets not exhaustively mapped"]},{"year":2018,"claim":"Regulation of WDR77 activity was established at two layers: SIRT7 deacetylation weakening PRMT5 binding, and PHF1/CRL4B reading the H4R3me2s mark to repress target genes.","evidence":"In vitro deacetylation, K3R/K243R mutagenesis and KO rescue; histone peptide binding and ChIP-seq for reader/effector complex","pmids":["30282801","29846670"],"confidence":"Medium","gaps":["Signals controlling SIRT7-WDR77 deacetylation unknown","Stoichiometry of PHF1-PRMT5-CRL4B unit not determined"]},{"year":2019,"claim":"Non-histone signaling control was demonstrated, with PRMT5-MEP50 methylation of GLI1 blocking its ubiquitin-ligase binding to drive Hedgehog pathway activation.","evidence":"Co-IP, methylation, fractionation, and ubiquitination assays","pmids":["30675521"],"confidence":"Medium","gaps":["GLI1 methylation site not pinpointed in this summary","Single-lab functional link awaits independent validation"]},{"year":2021,"claim":"WDR77 abundance was shown to be controlled by degradation pathways co-opted in disease, with HBx routing WDR77 to a DDB1 E3 ligase to relieve H4R3me2s repression on HBV cccDNA; a germline R198H mutation independently impairs PRMT5 binding in patients.","evidence":"Co-IP, ChIP, and HBV replication models; whole-exome sequencing, Co-IP and patient-tissue H4R3me2 Western","pmids":["34373747","34326253"],"confidence":"Medium","gaps":["Disease phenotype of R198H carriers not fully characterized","Generality of DDB1-mediated degradation beyond HBV unclear"]},{"year":2022,"claim":"The PRMT5:MEP50 interface was validated as druggable, and WDR77 was placed at active promoter regions co-occupying genes with MafB and β-catenin.","evidence":"Virtual screening and docking with W54-targeting inhibitor (Compound 17); reciprocal Co-IP and ChIP-seq of MafB/β-catenin/WDR77","pmids":["36206451","35482762"],"confidence":"Medium","gaps":["Functional consequence of MafB/β-catenin/WDR77 co-occupancy not mechanistically resolved","Selectivity window of interface inhibitors in vivo unclear"]},{"year":2023,"claim":"A methyltransferase-independent innate-immune role emerged, with WDR77 binding the MAVS proline-rich region through its WD2-WD4 module to suppress prion-like MAVS aggregation; the complex was also shown to restrict HEV and modify Lsm11/SmE.","evidence":"In vitro filament assays with recombinant proteins, domain mapping, myeloid KO mice; HEV replicon and R458K rescue; cryo-EM of Lsm10/Lsm11-methylosome","pmids":["37563140","37276230","37562960"],"confidence":"High","gaps":["How WDR77 toggles between methyltransferase and MAVS-suppressive roles unknown","Regulation of WDR77 recruitment to MAVS upon infection incomplete"]},{"year":2024,"claim":"Assembly of the active complex was shown to be promoted by accessory scaffolds, with TBL2 enhancing PRMT5-WDR77 interaction and downstream AKT phosphorylation.","evidence":"Proteomics, Co-IP, methyltransferase assay, in vivo and in vitro proliferation assays","pmids":["39499734"],"confidence":"Medium","gaps":["Whether TBL2 directly bridges the two subunits structurally unresolved","Link from methylation to AKT phosphorylation indirect"]},{"year":2025,"claim":"Multiple new regulatory and functional dimensions converged: RNF187 K118 ubiquitination degrades WDR77 to relieve EGR1 repression, C6orf223 stabilizes the complex, WDR77 acts with PRMT5/Ago2 to drive PDCD1 mRNA decay, and WDR77 directly coactivates AR cistromes in prostate cancer.","evidence":"Co-IP/MS ubiquitination mapping with EGR1 reporter; domain-mapped Co-IP and activity assay; RIP, RNA decay, T-cell conditional KO; ChIP-seq AR/WDR77 cistromes in organoids and PDX","pmids":["40197797","41090362","41623183","40934084"],"confidence":"Medium","gaps":["Interplay between competing stabilizers (TBL2, C6orf223) and degraders (RNF187) not integrated","How RNA-binding versus methyltransferase functions are partitioned in vivo unclear"]},{"year":null,"claim":"It remains unresolved how WDR77 localization, post-translational modification, and accessory-protein binding are coordinated to switch the complex between its methyltransferase, RNA-decay, transcriptional coactivator, and MAVS-suppressive activities in a given cell context.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking localization signals to functional switching","Quantitative competition between activating and degrading partners undefined","In vivo substrate hierarchy of the complex not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,0,20,23,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,5,7,11,12]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,3,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14,25,28,29]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[31]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,14,25,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,15,10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4,8,29]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,8,28,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,0,3,5,7,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,31,11,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,12,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,26,23,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,11,13,28]}],"complexes":["PRMT5-MEP50 (WDR77) methylosome","PRMT5/MEP50/pICln methylosome"],"partners":["PRMT5","MAVS","AR","TBL2","C6ORF223","RNF187","SIRT7","PHF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BQA1","full_name":"Methylosome protein WDR77","aliases":["Androgen receptor cofactor p44","Methylosome protein 50","MEP-50","WD repeat-containing protein 77","p44/Mep50"],"length_aa":342,"mass_kda":36.7,"function":"Non-catalytic component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones (PubMed:11756452). This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The methylosome complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage (PubMed:23071334)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BQA1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR77","classification":"Common 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DOMAIN OF RNA POLYMERASE II SUBUNIT A, PHOSPHATASE OF, SUBUNIT 1; CTDP1","url":"https://www.omim.org/entry/604927"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"fallopian 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\"X-ray crystallography with bound cofactor analog and peptide substrate\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with bound substrate and cofactor, defining hetero-octameric architecture and MEP50-PRMT5 interface\",\n      \"pmids\": [\"23071334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of the human PRMT5:MEP50 complex at 3.7 Å confirmed the 450 kDa hetero-octameric assembly with D2 internal symmetry; MEP50 subunits are arranged peripherally in complex with the PRMT5 N-terminal domain, consistent with the crystal structure.\",\n      \"method\": \"Single-particle cryo-electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent cryo-EM structure replicating and extending the crystal structure finding\",\n      \"pmids\": [\"29518110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEP50 is required for efficient histone methylation by PRMT5; the cross-dimer MEP50 is paired with its cognate PRMT5 to promote histone methylation. Mutation of a conserved arginine (Arg-42) on the MEP50 insertion loop increased the histone substrate Km, impairing PRMT5-MEP50 enzymatic efficiency. Neither full-length human PRMT5 nor the Xenopus PRMT5 catalytic domain has appreciable protein methyltransferase activity alone. Histones H4 and H3 bind PRMT5-MEP50 via histone fold interactions, and nucleosomes are not substrates.\",\n      \"method\": \"In vitro methylation assays including continuous kinetic assay, site-directed mutagenesis of MEP50 Arg-42, competition experiments, high-density histone peptide array interaction studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with mutagenesis and multiple orthogonal substrate-binding assays; establishes MEP50 as obligate activator positioning substrate\",\n      \"pmids\": [\"25713080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Xenopus Prmt5-Mep50 complex isolated from eggs specifically methylates pre-deposition histones H2A/H2A.X-F and H4, and the histone chaperone nucleoplasmin at Arg-187 (mono- and symmetric dimethylation). Nucleoplasmin modulates Prmt5-Mep50 activity directed toward histones, consistent with a regulatory role.\",\n      \"method\": \"Biochemical complex isolation, mass spectrometry identification of methylation sites, in vitro methylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted complex, MS-identified methylation sites, in vitro activity assays in single lab\",\n      \"pmids\": [\"22009756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRMT5-MEP50 catalyzes histone mono- and dimethylation (H3R2me1 and H4R3me2s) at chromatin of metastasis suppressor and EMT genes in response to TGFβ; H3R2me1 recruits WDR5 for concomitant H3K4 methylation and transcriptional activation, while H4R3me2s suppresses transcription at distinct loci.\",\n      \"method\": \"ChIP-seq, RNA-seq, knockdown of PRMT5 and MEP50, chromatin immunoprecipitation for histone marks\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP and knockdown with orthogonal transcriptomic readout; establishes mechanistic pathway linking PRMT5-MEP50 activity to TGFβ-driven transcriptional outcomes\",\n      \"pmids\": [\"27270440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nuclear PRMT5/WDR77 complex symmetrically dimethylates ZNF326 at Arg-175 (R175me2s), a modification lost upon PRMT5 or WDR77 depletion; loss of either subunit causes defects in alternative splicing including inclusion of A-T rich exons in target genes, phenocopying ZNF326 loss.\",\n      \"method\": \"Mass spectrometry identification of ZNF326 as substrate, Co-IP, methylation assays, RNA-seq splicing analysis, knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of substrate and modification site, biochemical validation, orthogonal splicing readout\",\n      \"pmids\": [\"28977470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT7 directly deacetylates WDR77 at Lys-3 and Lys-243; this deacetylation reduces WDR77's interaction with PRMT5, suppresses WDR77/PRMT5 transmethylase activity and H4R3me2 levels, and reduces colon cancer cell proliferation and migration. WDR77-2KR (K3R/K243R) variant showed reduced PRMT5 interaction and activity compared to WT.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K3R, K243R), H4R3me2 methylation assay, KO rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deacetylation, mutagenesis rescue, and KO cellular phenotype; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30282801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEP50/PRMT5 complex associates with GLI1 and methylates it; methylated GLI1 loses its ability to bind ubiquitin ligase ITCH/NUMB, resulting in nuclear accumulation and activation of GLI1 in the Hedgehog signaling pathway. HH signals enhance MEP50/PRMT5-GLI1 association.\",\n      \"method\": \"Co-immunoprecipitation, methylation assays, nuclear/cytoplasmic fractionation, ubiquitination assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and methylation demonstrated in cells, functional link to ubiquitination and nuclear accumulation established, single lab\",\n      \"pmids\": [\"30675521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHF1 N-terminal PHD finger recognizes H4R3me2s catalyzed by PRMT5-WDR77; PHF1, PRMT5-WDR77, and CRL4B complex (DDB1/CUL4B) reciprocally interact and collaborate as a functional unit to regulate target genes including E-cadherin and FBXW7.\",\n      \"method\": \"Co-IP, histone peptide binding assays, ChIP-seq, genome-wide target analysis, knockdown/overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and peptide binding for reader identification, ChIP-seq for targets; single lab\",\n      \"pmids\": [\"29846670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBx drives the cellular DDB1-containing E3 ubiquitin ligase to degrade WDR77 by recruiting WDR77 to the DDB1 complex; WDR77 degradation disables PRMT5-triggered H4R3me2s on cccDNA minichromosome, releasing transcriptional repression and promoting HBV replication.\",\n      \"method\": \"Co-IP, Western blot, ChIP assay, Southern/Northern blot, immunofluorescence in PHHs, HepG2-NTCP cells, and human liver-chimeric mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrated DDB1-WDR77 interaction, ChIP showed H4R3me2s on cccDNA, in vivo liver-chimeric mouse model; single lab\",\n      \"pmids\": [\"34373747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WDR77 binds to the proline-rich region of MAVS through its WD2-WD3-WD4 domain and inhibits the formation of prion-like MAVS filaments in vitro; upon virus infection, WDR77 is recruited to MAVS to prevent prion-like aggregation and downregulate RIG-I-MAVS signaling. Myeloid-specific Wdr77-deficient mice showed enhanced antiviral responses to negative-strand RNA viruses.\",\n      \"method\": \"Co-IP (MAVS-WDR77 interaction), in vitro filament formation assay with recombinant proteins, domain mapping, myeloid-specific KO mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstituted filament inhibition assay, domain-mapping, conditional KO mouse; multiple orthogonal methods\",\n      \"pmids\": [\"37563140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT5/WDR77 complex catalyzes methylation of HEV ORF1 replicase at Arg-458 (R458), impairing its replicase activity; virus bearing R458K mutation in ORF1 relieves PRMT5/WDR77-dependent restriction of HEV replication.\",\n      \"method\": \"SILAC/mass spectrometry identification, HEV replicon system, ORF1 methylation assay, R458K mutant virus rescue experiment\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of methylation site, mutant virus rescue confirms functional relevance; single lab\",\n      \"pmids\": [\"37276230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The PRMT5/MEP50/pICln methylosome methylates two arginine residues in the N-terminal region of Lsm11 and an N-terminal arginine in SmE (a modification distinct from spliceosomal snRNP biogenesis); the Lsm10-Lsm11 heterodimer interaction with the methylosome is mediated by PRMT5.\",\n      \"method\": \"Biochemical interaction assays, cryo-EM structural analysis of Lsm10/Lsm11-methylosome complex, in vitro methylation assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus in vitro methylation assays establishing interaction and substrate specificity; single lab\",\n      \"pmids\": [\"37562960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR77 germ-line missense mutation R198H impairs its interaction with PRMT5, and a splice-site mutation causes exon 6 skipping leading to markedly decreased mutant mRNA and obviously reduced H4R3me2 levels in mutation carriers.\",\n      \"method\": \"Whole-exome sequencing, Co-IP of R198H mutant vs WT for PRMT5 interaction, H4R3me2 Western blot in patient-derived tissue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived tissue validation with Co-IP interaction assay and histone mark readout; single study\",\n      \"pmids\": [\"34326253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p44/WDR77 contains functional nuclear localization signals (NLS) and nuclear exclusion signals (NES); site-directed mutagenesis of critical NLS residues abolished nuclear localization and transcriptional coactivator activity for AR. p44/WDR77 localizes cytoplasmically during prostate proliferation and translocates to the nucleus during differentiation.\",\n      \"method\": \"Subcellular localization assays spanning full ORF, NLS/NES mutagenesis, AR transcriptional reporter assays, MALDI-TOF/TOF mass spectrometry of NLS/NES-associated proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis linked to functional transcriptional readout and localization; single lab with multiple methods\",\n      \"pmids\": [\"21789256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cytoplasmic p44/WDR77 is essential for proliferation of prostate epithelial cells, while nuclear p44/WDR77 is required for cell differentiation and prostate-specific protein secretion; loss of p44/WDR77 leads to cell growth arrest partially through the p21-Rb signaling pathway.\",\n      \"method\": \"Conditional KO mouse model, re-expression rescue experiments, subcellular fractionation, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse and re-expression with defined cellular phenotypes and pathway readout; single lab\",\n      \"pmids\": [\"23145110\", \"22665061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of p44/WDR77 gene causes premature death with dramatic astrogliosis; loss of p44/WDR77 in astrocytes leads to growth arrest and astrocyte activation associated with upregulation of p21(Cip1) expression and NF-κB activation. Silencing p21(Cip1) or NF-κB p65 with shRNA abolished astrocyte activation and rescued growth inhibition.\",\n      \"method\": \"Gene knockout mouse model, shRNA knockdown epistasis experiment, Western blot, GFAP immunostaining\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KO + shRNA rescue) in mouse model placing WDR77 upstream of p21/NF-κB in astrocyte activation; single lab\",\n      \"pmids\": [\"22751923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p44/WDR77-null mouse prostates showed smaller glands with fewer branches, less differentiation, hyperproliferation, and altered expression of androgen-regulated genes, indicating that WDR77 plays a role in prostate growth and differentiation by modulating AR-target gene expression.\",\n      \"method\": \"Conditional KO mouse model, histology, gene expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined morphological and molecular phenotype; single lab\",\n      \"pmids\": [\"20519372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUZ12 interacts with MEP50 both in vitro and in vivo; MEP50 binds histone H2A selectively among core histones and mediates transcriptional repression by PRMT5.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assays, histone binding specificity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus in vitro binding; two orthogonal methods but single lab\",\n      \"pmids\": [\"16712789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MEP50 was identified as a novel FCP1-interacting protein by mass spectrometry of affinity-purified FCP1 complexes; FCP1 specifically interacts with components of spliceosomal U snRNPs, suggesting a role in linking transcription elongation with splicing.\",\n      \"method\": \"Affinity purification of epitope-tagged FCP1, mass spectrometry identification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single affinity-purification/MS identification, no mechanistic follow-up on MEP50 specifically\",\n      \"pmids\": [\"12560496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The structure of the PRMT5:MEP50 hetero-octameric complex provides a basis for understanding how MEP50's β-propeller positions substrate arginines toward the PRMT5 catalytic site; MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel defines a protein-protein interaction interface targetable by small molecules.\",\n      \"method\": \"Structural analysis review; small-molecule virtual screen + molecular docking validating the PPI interface\",\n      \"journal\": \"Sub-cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural interpretation review supported by docking; mechanistic detail about W54 later validated experimentally in PMID 36206451\",\n      \"pmids\": [\"28271477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Compound 17, a small-molecule PRMT5:MEP50 PPI inhibitor, disrupts MEP50 W54 burial into the PRMT5 TIM barrel hydrophobic pocket, selectively inhibiting PRMT5:MEP50 substrate methylation (IC50 <500 nM in cancer cells) and confirming the MEP50-PRMT5 interface as a druggable site.\",\n      \"method\": \"Virtual screening, molecular docking, in vitro methylation inhibition assays, RNA-seq\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro activity assay with selective inhibition, docking-guided mechanism; single lab\",\n      \"pmids\": [\"36206451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The interface between the TIM barrel of PRMT5 and adaptor proteins pICln, RioK1, and COPR5 involves the consensus amino acid sequence GQF[D/E]DA[E/D]; protein crystallography of the RioK1-derived peptide revealed a novel PPI site on PRMT5.\",\n      \"method\": \"Peptide truncation and mutation studies, protein crystallography\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of peptide at novel PPI site, validated by mutagenesis; single lab\",\n      \"pmids\": [\"33624332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBL2 acts as a scaffolding protein that promotes PRMT5 and WDR77 interaction; this enhances PRMT5 methyltransferase activity, leading to increased AKT phosphorylation in breast cancer cells.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, methyltransferase activity assay, in vivo and in vitro proliferation assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and methyltransferase assay with in vivo validation; single lab\",\n      \"pmids\": [\"39499734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR77 was identified as a protein interacting with TSC22D2 by yeast two-hybrid screening; the interaction was confirmed by co-immunoprecipitation and co-localization by immunofluorescence.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirmation of Y2H hit; no mechanistic follow-up\",\n      \"pmids\": [\"27337956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal region of p44/WDR77 (not the C-terminal WD40 domain) mediates interaction with the N-terminus of AR and full-length Smad1, forming a ternary AR-p44-Smad1 complex; both N- and C-terminal domains are needed for maximum AR transcriptional activation, while the central portion is required for nuclear p44-mediated prostate cancer growth inhibition.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assays, deletion mutagenesis, cell proliferation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP with luciferase functional readout and domain mutagenesis; single lab\",\n      \"pmids\": [\"23734213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Silencing p44/WDR77 increased cellular sensitivity to TGFβ signaling, inducing Smad2/3 phosphorylation, TGFβ-mediated transcription, and TGFβ2 and TβRII expression, suggesting WDR77 downregulates TGFβ ligand and receptor expression to restrict TGFβ pathway activity in proliferating cells.\",\n      \"method\": \"shRNA knockdown, phospho-Smad Western blot, TGFβ-responsive reporter assay, qPCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple molecular readouts; single lab, single study\",\n      \"pmids\": [\"24944016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF187 interacts with WDR77 and catalyzes lysine 48-linked polyubiquitination of WDR77 at K118, mediating its proteasomal degradation. Decreased WDR77 reduces H4R3me2s by PRMT5, relieving transcriptional repression of EGR1 and thereby promoting human spermatogonial stem cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination site mapping (K118), proteasome inhibitor experiments, H4R3me2s Western blot, EGR1 reporter\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS substrate identification, and site-specific ubiquitination with functional downstream readout; single lab\",\n      \"pmids\": [\"40197797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR77 directly interacts with AR and when this interaction is disrupted, AR-WDR77 complex formation is prevented, reducing AR DNA-binding, AR-dependent gene expression, and cell proliferation; AR and WDR77 cistromes overlap considerably at AR-regulated genes associated with aggressive prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq (AR and WDR77 cistromes), disruption of WDR77-AR interaction, organoid models, patient-derived xenograft growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and functional rescue in organoids; single lab\",\n      \"pmids\": [\"40934084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MafB, β-catenin, and WDR77 interact directly with each other and share similar genomic binding profiles; their common target sites are enriched just downstream of transcription initiation sites near paused RNA polymerase and the +1 nucleosome, and occupancy correlates with transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq for all three factors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and genome-wide ChIP-seq demonstrating co-occupancy; single lab\",\n      \"pmids\": [\"35482762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT5 is prone to aggregation when expressed at supra-stoichiometric levels relative to its obligate partner MEP50/WDR77; co-increased expression of PRMT5 and MEP50 mitigates protein aggregation induced by chromosomal instability, rendering cancer cells less sensitive to proteasome inhibitors.\",\n      \"method\": \"Protein aggregation assays, co-expression studies, proteasome inhibitor sensitivity assays in CIN models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, aggregation assay without full mechanistic dissection\",\n      \"pmids\": [\"bio_10.1101_2025.09.12.675799\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT5 acts as an RNA-binding protein in a methyltransferase activity-independent manner and promotes PDCD1 (PD-1) mRNA decay together with WDR77 and Argonaute2; the PRMT5/WDR77 complex binds a conserved AU-rich element in the PDCD1 3' UTR. IFN/STAT1 signaling transcriptionally activates PRMT5 and WDR77, enhancing their binding to PDCD1 mRNA. Conditional KO of WDR77 in T cells disrupts T cell effector function and sensitizes tumors to anti-PD-1 therapy.\",\n      \"method\": \"RNA immunoprecipitation, RNA decay assay, conditional KO mouse model, 3' UTR reporter assay, Co-IP with Argonaute2\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, RNA decay assay, conditional KO with immunological phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41623183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C6orf223 forms dimers through disulfide bonds; its N-terminal arginine-enriched region binds to the C-terminal negatively charged groove of PRMT5, stabilizing the PRMT5-MEP50 multiprotein complex and enhancing PRMT5 methyltransferase activity.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping, methyltransferase activity assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and activity assay; single lab\",\n      \"pmids\": [\"41090362\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR77/MEP50 is an obligate WD40 β-propeller cofactor of PRMT5 that forms a ~450 kDa hetero-octameric complex (four PRMT5 : four MEP50) in which MEP50's β-propeller contacts the PRMT5 N-terminal domain and positions protein substrates (histones H2A, H4, H3, nucleoplasmin, ZNF326, GLI1, HEV ORF1, Lsm11, SmE) toward the PRMT5 catalytic site for symmetric arginine dimethylation; PRMT5 alone has negligible activity, making MEP50 an obligate activator. WDR77 also functions as a MAVS-binding suppressor of prion-like MAVS aggregation to limit innate antiviral signaling, and as an mRNA-stability co-factor with PRMT5 to promote PDCD1 decay in T cells. Its activity is regulated post-translationally: SIRT7 deacetylates WDR77 at K3/K243 to weaken PRMT5 binding and reduce methyltransferase output, while RNF187 ubiquitinates WDR77 at K118 for proteasomal degradation and HBx co-opts DDB1 E3 ligase to degrade WDR77. Subcellular localization—controlled by NLS/NES sequences—dictates function: cytoplasmic WDR77 drives proliferation while nuclear WDR77 supports differentiation and AR/ER co-activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WDR77 (MEP50/p44) is an obligate WD40 β-propeller cofactor of the protein arginine methyltransferase PRMT5, assembling into a ~450 kDa hetero-octameric complex of four PRMT5 and four MEP50 subunits in which MEP50's seven-bladed β-propeller contacts the PRMT5 N-terminal domain and positions protein substrates toward the catalytic site [#0, #1]. PRMT5 has negligible methyltransferase activity alone, and MEP50 acts as an obligate activator: a conserved Arg-42 on the MEP50 insertion loop lowers the substrate Km, and the W54 residue buried in the PRMT5 TIM-barrel pocket defines the activating interface [#2, #20]. Through this complex WDR77 directs symmetric arginine dimethylation of histones (H2A, H4R3me2s, H3R2me1) and a broad set of non-histone substrates including nucleoplasmin, ZNF326, GLI1, the HEV ORF1 replicase, and Lsm11/SmE, thereby shaping chromatin marks, alternative splicing, Hedgehog signaling, and antiviral restriction [#3, #4, #5, #7, #11, #12]. The H4R3me2s mark deposited by PRMT5-WDR77 is read by the PHF1 PHD finger in concert with the CRL4B complex to repress target genes, and its loss de-represses transcription [#8]. WDR77 activity is tuned post-translationally: SIRT7 deacetylates WDR77 at K3/K243 to weaken PRMT5 binding, RNF187 ubiquitinates WDR77 at K118 (K48-linked) for proteasomal degradation, and the scaffold TBL2 and adaptor C6orf223 enhance PRMT5-WDR77 assembly and activity [#6, #27, #23, #32]. Independent of methyltransferase function, WDR77 binds the proline-rich region of MAVS via its WD2-WD3-WD4 module to suppress prion-like MAVS aggregation and dampen RIG-I-MAVS antiviral signaling, and partners with PRMT5 and Argonaute2 as an RNA-binding complex that drives PDCD1 (PD-1) mRNA decay in T cells [#10, #31]. Subcellular localization governed by NLS/NES sequences partitions WDR77 function—cytoplasmic WDR77 drives proliferation while nuclear WDR77 supports differentiation and acts as an androgen receptor coactivator [#14, #25, #28]. A germline WDR77 R198H missense mutation impairs PRMT5 binding and reduces cellular H4R3me2, linking WDR77 dysfunction to human disease [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Before its structural role was known, MEP50 was placed within PRMT5-dependent transcriptional repression, establishing it as a histone-binding partner of the methyltransferase.\",\n      \"evidence\": \"Co-IP and in vitro histone-binding assays showing SUZ12 and selective H2A binding\",\n      \"pmids\": [\"16712789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for histone selectivity\", \"Mechanism of repression not resolved at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The first reconstituted activity defined PRMT5-MEP50 substrate scope, showing the complex methylates pre-deposition histones and the chaperone nucleoplasmin, and that localization signals partition WDR77 function between proliferation and differentiation.\",\n      \"evidence\": \"Xenopus complex isolation with MS site mapping and in vitro methylation; NLS/NES mutagenesis with AR reporter assays\",\n      \"pmids\": [\"22009756\", \"21789256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish atomic architecture of the complex\", \"Determinants of nuclear vs cytoplasmic partitioning incompletely mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystallography solved the hetero-octameric architecture and revealed how MEP50's β-propeller engages the PRMT5 N-terminal domain to recognize substrate, answering how the cofactor enables catalysis.\",\n      \"evidence\": \"X-ray structure of human PRMT5:MEP50 with SAM analog and H4 peptide\",\n      \"pmids\": [\"23071334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify the kinetic contribution of MEP50 residues\", \"Non-histone substrate positioning not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In vivo knockout work established WDR77 as a regulator of proliferation versus differentiation, placing it upstream of the p21/Rb and NF-κB axes in prostate and astrocyte contexts.\",\n      \"evidence\": \"Conditional and germline KO mouse models, shRNA epistasis, subcellular fractionation, cell cycle analysis\",\n      \"pmids\": [\"23145110\", \"22665061\", \"22751923\", \"20519372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between localization and p21/NF-κB output unresolved\", \"Whether phenotypes depend on PRMT5 catalysis not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reconstitution with mutagenesis proved MEP50 is an obligate activator that positions substrate, pinpointing Arg-42 as a determinant of the substrate Km and showing PRMT5 alone is inactive.\",\n      \"evidence\": \"Kinetic in vitro methylation, MEP50 Arg-42 mutagenesis, histone peptide arrays\",\n      \"pmids\": [\"25713080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleosomes are not substrates—physiological substrate presentation unresolved\", \"Did not address non-histone substrate kinetics\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Chromatin-level studies connected PRMT5-MEP50 catalysis to opposing transcriptional outcomes, with H3R2me1 recruiting WDR5 for activation and H4R3me2s mediating repression downstream of TGFβ.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, PRMT5/MEP50 knockdown; separate knockdown TGFβ-sensitivity assays\",\n      \"pmids\": [\"27270440\", \"24944016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Locus-specific determinants of activation vs repression unclear\", \"Recruitment of the complex to specific genes not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Substrate scope was extended beyond histones, with ZNF326 methylation at R175 linking WDR77 to alternative splicing fidelity.\",\n      \"evidence\": \"MS substrate identification, Co-IP, methylation and RNA-seq splicing analysis with knockdown\",\n      \"pmids\": [\"28977470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How methylation alters ZNF326 function mechanistically not resolved\", \"Breadth of splicing targets not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Regulation of WDR77 activity was established at two layers: SIRT7 deacetylation weakening PRMT5 binding, and PHF1/CRL4B reading the H4R3me2s mark to repress target genes.\",\n      \"evidence\": \"In vitro deacetylation, K3R/K243R mutagenesis and KO rescue; histone peptide binding and ChIP-seq for reader/effector complex\",\n      \"pmids\": [\"30282801\", \"29846670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling SIRT7-WDR77 deacetylation unknown\", \"Stoichiometry of PHF1-PRMT5-CRL4B unit not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Non-histone signaling control was demonstrated, with PRMT5-MEP50 methylation of GLI1 blocking its ubiquitin-ligase binding to drive Hedgehog pathway activation.\",\n      \"evidence\": \"Co-IP, methylation, fractionation, and ubiquitination assays\",\n      \"pmids\": [\"30675521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GLI1 methylation site not pinpointed in this summary\", \"Single-lab functional link awaits independent validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"WDR77 abundance was shown to be controlled by degradation pathways co-opted in disease, with HBx routing WDR77 to a DDB1 E3 ligase to relieve H4R3me2s repression on HBV cccDNA; a germline R198H mutation independently impairs PRMT5 binding in patients.\",\n      \"evidence\": \"Co-IP, ChIP, and HBV replication models; whole-exome sequencing, Co-IP and patient-tissue H4R3me2 Western\",\n      \"pmids\": [\"34373747\", \"34326253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease phenotype of R198H carriers not fully characterized\", \"Generality of DDB1-mediated degradation beyond HBV unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The PRMT5:MEP50 interface was validated as druggable, and WDR77 was placed at active promoter regions co-occupying genes with MafB and β-catenin.\",\n      \"evidence\": \"Virtual screening and docking with W54-targeting inhibitor (Compound 17); reciprocal Co-IP and ChIP-seq of MafB/β-catenin/WDR77\",\n      \"pmids\": [\"36206451\", \"35482762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MafB/β-catenin/WDR77 co-occupancy not mechanistically resolved\", \"Selectivity window of interface inhibitors in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A methyltransferase-independent innate-immune role emerged, with WDR77 binding the MAVS proline-rich region through its WD2-WD4 module to suppress prion-like MAVS aggregation; the complex was also shown to restrict HEV and modify Lsm11/SmE.\",\n      \"evidence\": \"In vitro filament assays with recombinant proteins, domain mapping, myeloid KO mice; HEV replicon and R458K rescue; cryo-EM of Lsm10/Lsm11-methylosome\",\n      \"pmids\": [\"37563140\", \"37276230\", \"37562960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WDR77 toggles between methyltransferase and MAVS-suppressive roles unknown\", \"Regulation of WDR77 recruitment to MAVS upon infection incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assembly of the active complex was shown to be promoted by accessory scaffolds, with TBL2 enhancing PRMT5-WDR77 interaction and downstream AKT phosphorylation.\",\n      \"evidence\": \"Proteomics, Co-IP, methyltransferase assay, in vivo and in vitro proliferation assays\",\n      \"pmids\": [\"39499734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TBL2 directly bridges the two subunits structurally unresolved\", \"Link from methylation to AKT phosphorylation indirect\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple new regulatory and functional dimensions converged: RNF187 K118 ubiquitination degrades WDR77 to relieve EGR1 repression, C6orf223 stabilizes the complex, WDR77 acts with PRMT5/Ago2 to drive PDCD1 mRNA decay, and WDR77 directly coactivates AR cistromes in prostate cancer.\",\n      \"evidence\": \"Co-IP/MS ubiquitination mapping with EGR1 reporter; domain-mapped Co-IP and activity assay; RIP, RNA decay, T-cell conditional KO; ChIP-seq AR/WDR77 cistromes in organoids and PDX\",\n      \"pmids\": [\"40197797\", \"41090362\", \"41623183\", \"40934084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between competing stabilizers (TBL2, C6orf223) and degraders (RNF187) not integrated\", \"How RNA-binding versus methyltransferase functions are partitioned in vivo unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how WDR77 localization, post-translational modification, and accessory-protein binding are coordinated to switch the complex between its methyltransferase, RNA-decay, transcriptional coactivator, and MAVS-suppressive activities in a given cell context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking localization signals to functional switching\", \"Quantitative competition between activating and degrading partners undefined\", \"In vivo substrate hierarchy of the complex not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 0, 20, 23, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 5, 7, 11, 12]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 3, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14, 25, 28, 29]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 14, 25, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 15, 10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4, 8, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 8, 28, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 0, 3, 5, 7, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 31, 11, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 12, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 26, 23, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 11, 13, 28]}\n    ],\n    \"complexes\": [\n      \"PRMT5-MEP50 (WDR77) methylosome\",\n      \"PRMT5/MEP50/pICln methylosome\"\n    ],\n    \"partners\": [\n      \"PRMT5\",\n      \"MAVS\",\n      \"AR\",\n      \"TBL2\",\n      \"C6orf223\",\n      \"RNF187\",\n      \"SIRT7\",\n      \"PHF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}