{"gene":"WDR5","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"WDR5 directly associates with histone H3 di- and trimethylated at K4 and with H3-K4-dimethylated nucleosomes. WDR5 is required for binding of the MLL1/MLL2/hSet1 methyltransferase complex to the K4-dimethylated H3 tail and for global H3K4 trimethylation. Depletion of WDR5 in X. laevis disrupts HOX gene expression and causes developmental defects.","method":"Co-immunoprecipitation, pull-down assays with modified histone peptides, RNAi knockdown in Xenopus, ChIP","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, in vivo knockdown with defined phenotypic readout, replicated across multiple labs subsequently","pmids":["15960974"],"is_preprint":false},{"year":2006,"finding":"High-resolution X-ray crystal structures of WDR5 alone and complexed with unmodified, mono-, di-, and trimethylated H3K4 peptides reveal that WDR5 does not read the methylation state of K4 directly; instead it presents the K4 side chain for further methylation by SET1-family complexes.","method":"X-ray crystallography (high-resolution structures), peptide binding assays","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with comprehensive methylation state analysis, foundational structural study replicated and cited widely","pmids":["16829959"],"is_preprint":false},{"year":2008,"finding":"A conserved arginine-containing 'Win' motif in MLL1 (Arg-3765) binds into the same arginine-binding pocket on WDR5 that was previously suggested to bind histone H3. MLL1 Win peptide is preferentially recognized by WDR5, and this interaction is essential for MLL1 core complex assembly and H3K4 dimethylation activity.","method":"1.7 Å X-ray crystal structure of WDR5-MLL1 Win peptide complex, thermodynamic binding experiments (ITC/fluorescence)","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure plus thermodynamic binding data in single rigorous study","pmids":["18829459"],"is_preprint":false},{"year":2009,"finding":"WDR5 is recruited to the mitochondrial outer membrane protein VISA in a viral-infection-dependent manner. Upon viral infection, WDR5 translocates from the nucleus to mitochondria and is essential for assembly of the VISA-associated signaling complex; knockdown of WDR5 impairs virus-triggered activation of IRF3 and NF-κB and reduces IFNB1 transcription.","method":"Biochemical purification, co-immunoprecipitation, subcellular fractionation, siRNA knockdown with reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional knockdown in single lab with multiple orthogonal methods","pmids":["20080758"],"is_preprint":false},{"year":2011,"finding":"WDR5 interacts with the pluripotency transcription factor Oct4 and overlapping genome-wide gene regulatory functions between Oct4 and WDR5 were demonstrated. WDR5 is required for ES cell self-renewal and efficient formation of induced pluripotent stem cells.","method":"Co-immunoprecipitation, genome-wide ChIP-seq, transcriptome analysis, RNAi knockdown, iPSC reprogramming assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genome-wide binding data and functional loss-of-function in multiple orthogonal assays","pmids":["21477851"],"is_preprint":false},{"year":2011,"finding":"Under hypoxia, HDAC3 interacts with WDR5, recruits the histone methyltransferase complex to increase H3K4-specific HMT activity, and activates mesenchymal gene expression to promote EMT. Knockdown of WDR5 abolishes mesenchymal gene activation but not epithelial gene repression during hypoxia.","method":"Co-immunoprecipitation, RNAi knockdown, H3K4 methyltransferase activity assay, gene expression analysis","journal":"Molecular Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, functional knockdown with specific phenotypic readout (mesenchymal vs epithelial gene regulation), single lab","pmids":["21884981"],"is_preprint":false},{"year":2012,"finding":"Peptidomimetic inhibitors based on the MLL1 Win motif bind WDR5 with Ki < 1 nM and function as potent antagonists of MLL1 H3K4 methyltransferase activity in a fully reconstituted in vitro assay. Co-crystal structures of two peptidomimetics with WDR5 establish the structural basis for high-affinity binding.","method":"In vitro reconstituted H3K4 methyltransferase assay, co-crystal structures, binding affinity measurements, cell-based leukemia proliferation assays","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro enzymatic assay plus co-crystal structures with multiple compounds, rigorous mechanistic validation","pmids":["23210835"],"is_preprint":false},{"year":2013,"finding":"Small-molecule antagonists of the WDR5 peptide-binding pocket (Win site) bind with Kd ~450 nM and inhibit the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations, consistent with WDR5 directly stabilizing the MLL multiprotein complex.","method":"Structural analysis, biophysical binding assays, in vitro H3K4 methyltransferase assay","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted enzymatic assay plus structural/biophysical characterization in single rigorous study","pmids":["22989411"],"is_preprint":false},{"year":2013,"finding":"Glucagon/cAMP signaling causes dephosphorylation of CRTC2, which promotes recruitment of KAT2B and WDR5 to gluconeogenic gene promoters, increasing H3K9Ac and H3K4 methylation to activate hepatic gluconeogenesis. Depletion of WDR5 decreases gluconeogenic gene expression and blood glucose levels.","method":"Mouse models, in vitro chromatin assays, ChIP, siRNA knockdown, pharmacological inhibition","journal":"The Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, in vivo mouse models, and in vitro assays in single lab with multiple orthogonal methods","pmids":["24051374"],"is_preprint":false},{"year":2014,"finding":"A specific RNA-binding pocket on WDR5 (mutated by F266A) selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. The F266A mutant cannot accumulate on chromatin, is defective in H3K4me3 maintenance and gene activation, and cannot sustain ESC self-renewal. A family of ESC mRNAs and lncRNAs interact with wild-type but not F266A WDR5, indicating RNA binding is required for WDR5 chromatin occupancy.","method":"Structure-guided mutagenesis, RNA immunoprecipitation, complementation assays in ESCs, ChIP, RNA-seq","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis distinguishing RNA-binding from complex assembly, multiple orthogonal functional readouts in a single rigorous study","pmids":["24521543"],"is_preprint":false},{"year":2014,"finding":"WDR5 is recruited into the NSL (non-specific lethal) complex via conserved linear motifs of KANSL1 and KANSL2. Structural analysis shows the KANSL1/WDR5/KANSL2 subcomplex architecture. The KANSL1–WDR5 interaction is required for proper NSL complex assembly, efficient recruitment to target promoters, and fly viability. WDR5 interactions with NSL and MLL/COMPASS complexes are mutually exclusive.","method":"Structural analysis (X-ray crystallography), biochemical interaction mapping, structure-based KANSL1 mutants in transgenic flies, ChIP","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus structure-based mutagenesis with in vivo functional validation in Drosophila","pmids":["24788516"],"is_preprint":false},{"year":2015,"finding":"MYC binds WDR5 via an evolutionarily conserved 'MYC box IIIb' motif that engages a shallow hydrophobic cleft (WBM site) on WDR5. Structure-guided mutations disrupting this interaction attenuate MYC binding at ~80% of its chromosomal locations and disable MYC-driven iPSC formation and tumorigenesis.","method":"Co-immunoprecipitation, X-ray crystal structure of WDR5–MYC peptide complex, ChIP-seq, structure-guided mutagenesis, iPSC formation assay, xenograft tumor model","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus genome-wide ChIP-seq plus in vivo tumor model in single rigorous study","pmids":["25818646"],"is_preprint":false},{"year":2015,"finding":"C/EBPα p30 (but not p42) isoform preferentially interacts with WDR5 in AML. p30-bound genomic regions are enriched for MLL-dependent H3K4me3. WDR5 downregulation inhibits p30-dependent cell proliferation and restores myeloid differentiation. OICR-9429, a small-molecule antagonist of the WDR5–MLL interaction, selectively inhibits proliferation and induces differentiation in p30-expressing AML cells.","method":"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, pharmacological inhibition with OICR-9429, differentiation assays","journal":"Nature Chemical Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, functional knockdown and pharmacological validation across multiple AML models","pmids":["26167872"],"is_preprint":false},{"year":2015,"finding":"WDR5 localizes to the midbody and associates with PRC1 and CYK4/MKLP1. Knockdown of WDR5 impairs abscission, increases multinucleated cells, slows secondary ingression formation, and increases midbody microtubule resistance to depolymerization. Mutations disrupting the central arginine-binding cavity of WDR5 abolish midbody localization.","method":"Immunofluorescence localization, RNAi knockdown, live-cell imaging, microtubule depolymerization assays, mutagenesis","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, mutagenesis, single lab with multiple orthogonal methods","pmids":["25666610"],"is_preprint":false},{"year":2015,"finding":"WDR5 has a unique role in the MLL3 complex: unlike MLL1, the MLL3 SET domain assembles with RbBP5/Ash2L independently of the Win motif–WDR5 interaction. WDR5 inhibits the monomethylation activity of the MLL3 core complex in a Win-motif-dependent manner. Solution structures by SAXS show similar overall topologies with or without WDR5.","method":"In vitro binding assays, in vitro methyltransferase activity assay, small-angle X-ray scattering (SAXS), mutagenesis","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted enzymatic assay plus SAXS structures plus mutagenesis in single rigorous study","pmids":["26324722"],"is_preprint":false},{"year":2016,"finding":"The Win motif is necessary for interaction of WDR5 with all human SET1 family members. Mutation of the Win motif–WDR5 interface severely disrupts assembly and activity of MLL1 and SETd1A complexes but only modestly disrupts MLL2/4 and SETd1B complexes. For MLL3, WDR5 absence leads to enhanced monomethylation activity. A peptidomimetic (Kd ~3 nM) selectively inhibits MLL1 and SETd1A core complexes within the SET1 family.","method":"In vitro binding assays, in vitro H3K4 methyltransferase assays, mutagenesis, peptidomimetic inhibitor design","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro enzymatic assays across all SET1 family members with mutagenesis, multiple orthogonal methods","pmids":["27563068"],"is_preprint":false},{"year":2016,"finding":"Cbx8 associates with non-PRC1 complexes containing WDR5. This Cbx8–WDR5 association maintains H3K4me3 levels on Notch-network gene promoters to regulate Notch signaling and promote mammary tumorigenesis.","method":"Co-immunoprecipitation, ChIP-seq for H3K4me3, RNAi knockdown, tumorsphere formation assay","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus ChIP-seq and functional assays, single lab","pmids":["27346354"],"is_preprint":false},{"year":2017,"finding":"MLL/WDR5 complex localizes to the mitotic spindle apparatus. WDR5 directly interacts with Kif2A via a conserved Win motif in Kif2A, and this interaction regulates Kif2A localization to the spindle during mitosis. Loss of MLL/WDR5 function causes chromosome congression defects and compromised spindle formation.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, in vitro binding assay with Win motif peptide","journal":"Developmental Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated in vitro, localization shown by IF, functional loss-of-function with specific mitotic phenotype, single lab","pmids":["28633016"],"is_preprint":false},{"year":2017,"finding":"TWIST1 forms a complex with WDR5 and the lncRNA Hottip. TWIST1 overexpression leads to co-enrichment of TWIST1 and WDR5 and increased H3K4me3 at the Hoxa9 promoter in a WDR5-dependent manner. WDR5 and Hottip expression are required for TWIST1-induced HOXA9 upregulation and invasive/migratory phenotypes.","method":"Co-immunoprecipitation, ChIP-seq, siRNA/shRNA knockdown, cell invasion/migration assays, in vivo metastasis model","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and functional knockdown with specific readouts, single lab","pmids":["28484075"],"is_preprint":false},{"year":2018,"finding":"WIN site inhibitors displace WDR5 from chromatin at a specific cohort of loci enriched for ribosomal protein genes, causing decreased expression of associated genes, translational inhibition, nucleolar stress, and p53 induction.","method":"Potent WIN site inhibitor development, ChIP-seq, RNA-seq, translational assays, p53 pathway analysis","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus mechanistic pathway dissection with multiple functional readouts, replicated in subsequent studies","pmids":["30865883"],"is_preprint":false},{"year":2018,"finding":"WDR5, independently of chromatin modification, regulates cell polarity, nuclear deformability, and migration of lymphocytes. Actomyosin contractility via MLCK-mediated myosin phosphorylation controls WDR5 interaction with other methyltransferase complex components, which in turn upregulates H3K4 methylation in 3D environments to reduce nuclear stiffness.","method":"Live imaging, FRAP, RNAi knockdown, atomic force microscopy, nuclear particle tracking, nuclear swelling experiments, pharmacological inhibition of MLCK","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biophysical measurements of nuclear mechanics, localization and functional consequences, single lab with multiple orthogonal methods","pmids":["29987046"],"is_preprint":false},{"year":2018,"finding":"In multiciliated cells, WDR5 has a chromatin-independent scaffolding role: it binds to basal bodies, migrates apically, and F-actin organizes around WDR5. WDR5 stabilizes F-actin to maintain the apical lattice architecture required for basal body distribution and ciliogenesis.","method":"RNAi knockdown in Xenopus MCCs, live imaging, actin monomer trap (G-actin sequestration), immunofluorescence localization","journal":"Developmental Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to basal bodies, functional consequence of knockdown, actin dynamics assay, single lab","pmids":["30205038"],"is_preprint":false},{"year":2018,"finding":"WDR5 is recruited to cytoplasmic viral inclusion bodies of measles virus and is found in complexes containing viral RNA replication proteins. WDR5 deficiency decreases viral protein production and infectious virus yields, indicating WDR5 promotes viral replication.","method":"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, viral titer assays","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with viral proteins, direct localization to inclusion bodies, functional knockdown, single lab","pmids":["29237839"],"is_preprint":false},{"year":2018,"finding":"SETD6 catalyzes monomethylation of WDR5 at lysines K207 and K325. Disrupting this methylation via K207R/K325R double mutation attenuates WDR5 promotion of breast cancer cell proliferation and migration, and partially reduces global H3K4me3 levels, without affecting MLL/SET1 complex assembly.","method":"Mass spectrometry identification of methylation sites, in vitro methyltransferase assay, site-directed mutagenesis, cell proliferation and migration assays, western blot for H3K4me3","journal":"Oncology Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus mutagenesis plus functional readout, single lab","pmids":["30226578"],"is_preprint":false},{"year":2018,"finding":"WDR5 facilitates HCMV capsid nuclear egress: WDR5 knockdown impairs formation of the viral nuclear egress complex, reduces infoldings of the inner nuclear membrane, reduces capsid association with these infoldings, and decreases cytoplasmic capsids, resulting in dramatically reduced infectious virus titers.","method":"RNAi knockdown, transmission electron microscopy of nuclear membrane morphology, infectious titer assays, overexpression rescue","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific subcellular morphological phenotype and functional titer readout with knockdown and rescue, single lab","pmids":["29437978"],"is_preprint":false},{"year":2018,"finding":"WDR5 localizes to the bases of cilia in the LR organizer and regulates foxj1 expression in monociliated cells. WDR5 has a dual role in left-right patterning: a chromatin/H3K4-dependent role in ciliogenesis via foxj1, and an H3K4-independent role revealed by a specific WDR5 mutant.","method":"WDR5 morpholino knockdown in Xenopus, rescue with foxj1, WDR5 H3K4-binding mutant analysis, immunofluorescence localization to cilia bases","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with genetic rescue, mutant analysis separating chromatin-dependent and independent roles, single lab","pmids":["30377171"],"is_preprint":false},{"year":2019,"finding":"WIN site inhibitors kill MLL-rearranged cancer cells not through changes in histone methylation but by displacing WDR5 from chromatin at protein synthesis (ribosomal protein) genes, causing translational inhibition and p53 induction via nucleolar stress.","method":"ChIP-seq, RNA-seq, translational reporters, p53 pathway analysis, pharmacological WIN site inhibitors","journal":"Epigenetics Insights","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established with genome-wide data and multiple assays, single lab (consistent with independent Cell Reports 2019 paper)","pmids":["31360909"],"is_preprint":false},{"year":2019,"finding":"PTENα and PTENβ directly interact with WDR5 to promote H3K4 trimethylation and maintain a tumor-promoting transcriptional signature. USP9X deubiquitinates and FBXW11 ubiquitinates PTENα at K235/K239 to regulate PTENα/β stability, which in turn controls WDR5-dependent H3K4me3.","method":"Co-immunoprecipitation, ChIP-seq, ubiquitination assays, in vitro binding assays, knockdown/overexpression","journal":"Nature Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP-seq with functional pathway placement, single lab with multiple orthogonal methods","pmids":["31685992"],"is_preprint":false},{"year":2020,"finding":"H3R2 arginine methylation acts as a binary switch regulating WDR5 interaction: H3R2me2a (PRMT6-catalyzed) prevents WDR5 binding, whereas H3R2me0, -me1, and -me2s (PRMT5-catalyzed) are equally permissive for WDR5 interaction. Crystal structures of WDR5 with unmodified and methylated arginine/H3R2 peptides provide structural basis for this selectivity.","method":"Quantitative binding analysis, X-ray crystal structures of WDR5 with me0/me1/me2s arginine and H3R2me1 peptide","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures combined with quantitative binding assays, rigorous biochemical characterization of methylation-state discrimination","pmids":["32207970"],"is_preprint":false},{"year":2020,"finding":"WDR5 directly interacts with p53, enabling their co-recruitment to and regulation of genes controlling cell proliferation and fate. In mESCs, WDR5 binds to and activates neural genes via an RbBP5-dependent process; after prolonged inhibition and rescue, WDR5 targets mesoderm lineage genes in a p53-dependent fashion.","method":"Co-immunoprecipitation of WDR5–p53, ChIP-seq, ATAC-seq, Wdr5 conditional knockout and rescue in mESCs","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genome-wide chromatin assays and genetic rescue, single lab with multiple orthogonal methods","pmids":["31940490"],"is_preprint":false},{"year":2016,"finding":"PAS kinase (Pask) phosphorylates Wdr5 to regulate myoblast differentiation. Pask stimulates conversion of repressive H3K4me1 to activating H3K4me3 on the Myog promoter via Wdr5 phosphorylation, enhancing MyoD accessibility and transcriptional activation of myogenin to initiate muscle differentiation.","method":"In vitro kinase assay (Pask phosphorylates Wdr5), ChIP for H3K4me1/me3, genetic knockdown/knockout in myoblasts, Myog promoter activity assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus ChIP plus functional differentiation assays, single lab","pmids":["27661449"],"is_preprint":false},{"year":2021,"finding":"WDR5 functions as a 'reader' for histone H3Q5 serotonylation (H3Q5ser). Crystal structures of WDR5 complexed with H3Q5ser and H3K4me3Q5ser peptides show the serotonyl group accommodated in a shallow surface pocket. WDR5 recognition of H3Q5ser promotes H3K4me3 deposition; disruption of this interaction impairs H3K4me3 and reduces expression of cancer-promoting genes in neuroblastoma cells.","method":"X-ray crystallography (WDR5–H3Q5ser and –H3K4me3Q5ser complexes), binding assays, ChIP-seq, cell-based functional assays in neuroblastoma cells","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus functional validation in cells with multiple orthogonal methods in single rigorous study","pmids":["34144982"],"is_preprint":false},{"year":2021,"finding":"WDR5 is a substrate of the SCF-FBXW7 E3 ubiquitin ligase. WDR5 interacts with FBXW7 in vivo and in vitro; FBXW7 mediates WDR5 ubiquitination and proteasomal degradation during prolonged mitotic arrest. WDR5 depletion reduces mitotic slippage, establishing WDR5 as a pro-slippage factor downstream of FBXW7.","method":"Co-immunoprecipitation, in vitro binding assay, in vitro ubiquitination assay, proteasome inhibitor experiments, RNAi knockdown","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitination reconstitution plus Co-IP plus functional slippage assay, single lab","pmids":["36395886"],"is_preprint":false},{"year":2021,"finding":"A selective WDR5 degrader (MS67) designed via crystal structures of WDR5–degrader–VHL ternary complexes potently depletes WDR5, decreases chromatin-bound MLL complex components and c-MYC, suppresses WDR5-regulated gene transcription more effectively than PPI inhibitors, and inhibits MLL-rearranged AML patient cell growth in vivo.","method":"Crystal structures of ternary WDR5–PROTAC–VHL complexes, biophysical cooperativity measurements, ChIP, RNA-seq, in vitro and in vivo AML patient-derived models","journal":"Science Translational Medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures of ternary complexes plus in vitro and in vivo functional validation with multiple orthogonal methods","pmids":["34586829"],"is_preprint":false},{"year":2022,"finding":"WDR5 promotes cell growth in breast cancer by increasing ribosomal gene expression and translation efficiency in a KMT2 (MLL)-independent manner. Pharmacological inhibition or degradation of WDR5 impedes cellular translation rate; combination with mTOR inhibitors potently suppresses translation and proliferation.","method":"In vivo genetic screen, RNAi knockdown, ribosome profiling/translation efficiency assays, pharmacological inhibitor/degrader treatment, mTOR inhibitor combination studies","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo screen plus mechanistic translational assays, KMT2-independence established, single lab with multiple orthogonal methods","pmids":["36043466"],"is_preprint":false},{"year":2023,"finding":"WDR5 is required for DUX4 expression in FSHD muscle cells through its interaction with the lncRNA DBE-T (identified by affinity purification/proteomics). WDR5 inhibition/knockdown rescues cell viability and myogenic differentiation of FSHD patient cells without harming healthy donor cells.","method":"Affinity purification + proteomics (DBE-T interactors), RNAi knockdown, pharmacological WDR5 inhibition, differentiation assays in primary FSHD muscle cells","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification/proteomics for interaction identification plus functional knockdown and pharmacological validation, single lab","pmids":["37021550"],"is_preprint":false},{"year":2024,"finding":"WDR5 WIN site inhibition in MLL-rearranged leukemia cells suppresses ribosome protein gene (RPG) transcription, causes ribosome depletion and a broad translational choke, and inactivates the p53 antagonist MDM4 through changes in alternative mRNA splicing, activating p53 and killing cancer cells. WIN site inhibitors are synergistic with venetoclax and BET-bromodomain inhibitors.","method":"Multi-omics (ChIP-seq, RNA-seq, ribosome profiling, proteomics), alternative splicing analysis, drug synergy assays in MLL-rearranged cell lines","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated multi-omics approach with multiple orthogonal methods delineating mechanism, synergy with orthogonal drugs, consistent with prior Cell Reports 2019 findings","pmids":["38682900"],"is_preprint":false},{"year":2024,"finding":"Crystal structures of DCAF1–PROTAC–WDR5 ternary complexes reveal that DCAF1 loops provide surface plasticity enabling recruitment of WDR5 as a substrate for DCAF1-containing CUL4 E3 ligases. Four DCAF1-based PROTACs achieve WDR5 degradation, with the ternary structures informing substrate specificity of DCAF1.","method":"High-resolution X-ray crystal structures of ternary DCAF1–PROTAC–WDR5 complexes, WDR5 degradation assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures of ternary complexes with functional degradation validation in single rigorous study","pmids":["39580491"],"is_preprint":false},{"year":2003,"finding":"WDR5 (originally identified as BIG-3, a BMP-2-induced gene) is expressed in proliferating and hypertrophic chondrocytes in the developing growth plate and accelerates chondrocyte differentiation in vitro when stably overexpressed, increasing matrix proteoglycan synthesis, alkaline phosphatase, osteopontin, and mineralized matrix formation.","method":"Stable transfection/overexpression in chondrogenic ATDC5 cells, biochemical differentiation markers, BMP-2 treatment","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function with multiple differentiation readouts in single lab; foundational identification paper for BIG-3/WDR5 in chondrocytes","pmids":["14657013"],"is_preprint":false},{"year":2008,"finding":"WDR5 knockdown in MC3T3-E1 osteoblasts markedly inhibits osteoblast differentiation (reduced alkaline phosphatase, Runx-2, osteocalcin, mineralized matrix), reduces H3K4me3, and disrupts the canonical Wnt signaling pathway by decreasing Wnt expression and nuclear β-catenin. ChIP demonstrates WDR5 occupancy at the Wnt1 promoter and canonical Wnt response elements on c-myc and Runx-2 promoters.","method":"Stable siRNA knockdown, alkaline phosphatase assay, mineralization assay, qPCR, western blot, ChIP","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple differentiation readouts plus ChIP for direct promoter occupancy, single lab","pmids":["18201971"],"is_preprint":false},{"year":2016,"finding":"Regulation of DNA replication: WDR5 (as part of MLL–WDR5–RBBP5 complex) co-localizes with ORC and MCM2-7 at replication origins. WDR5 or RBBP5 knockdown suppresses DNA re-replication and chromosomal polyploidy, reduces H3K4me at origins, and suppresses MCM2-7 recruitment to origins.","method":"siRNA knockdown, ChIP at replication origins, flow cytometry for polyploidy, H2AX checkpoint assays","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at replication origins plus functional replication and polyploidy assays with knockdown, single lab","pmids":["27744293"],"is_preprint":false}],"current_model":"WDR5 is a WD40-repeat scaffold protein that operates at multiple levels of chromatin regulation and beyond: its central arginine-binding cavity (WIN site) recruits WDR5 to all SET1/MLL family histone H3K4 methyltransferase complexes by engaging a conserved Win motif in catalytic subunits, positioning the K4 side chain for methylation rather than reading the methylation state directly; a distinct surface pocket (WBM site) mediates direct interaction with MYC and other transcription factors to tether them to chromatin; a separate RNA-binding pocket is required for WDR5 chromatin accumulation and H3K4me3 maintenance; and WDR5 additionally reads H3Q5 serotonylation and H3R2 methylation status via its central cavity. Beyond chromatin, WDR5 localizes to the midbody to promote cytokinetic abscission, to the mitotic spindle to regulate Kif2A-dependent chromosome congestion, to basal bodies in multiciliated cells to stabilize F-actin architecture, to mitochondria during viral infection to assemble the VISA antiviral signaling complex, and to replication origins to support MCM loading. WDR5 is itself regulated post-translationally by SETD6-mediated lysine methylation (K207/K325) and FBXW7-mediated ubiquitination and proteasomal degradation during mitotic arrest, while upstream kinase PASK phosphorylates WDR5 to drive H3K4me1→me3 conversion at differentiation gene promoters."},"narrative":{"mechanistic_narrative":"WDR5 is a WD40-repeat scaffold protein that organizes histone H3K4 methylation by the SET1/MLL family of methyltransferases and tethers these and other transcriptional regulators to chromatin [PMID:15960974, PMID:27563068]. Rather than reading the K4 methylation state, WDR5 presents the H3K4 side chain for catalysis, and its central arginine-binding cavity (the WIN site) instead engages a conserved arginine-containing Win motif in the catalytic subunits—first defined for MLL1—to drive core-complex assembly and H3K4 dimethylation [PMID:16829959, PMID:18829459]. The Win motif is required for WDR5 association with all human SET1-family members, though WDR5 dependence varies by complex: it is critical for MLL1 and SETd1A but only modestly required for MLL2/4 and SETd1B, and it restrains rather than promotes MLL3 monomethylation activity [PMID:27563068, PMID:26324722]. WDR5 also recruits MYC to ~80% of its chromosomal sites through a distinct shallow hydrophobic cleft (the WBM site) that binds the MYC box IIIb motif, and is incorporated into the NSL complex via KANSL1/KANSL2 linear motifs in a manner mutually exclusive with MLL/COMPASS engagement [PMID:25818646, PMID:24788516]. A separate RNA-binding pocket is required for WDR5 chromatin accumulation, H3K4me3 maintenance, and ESC self-renewal independently of complex assembly [PMID:24521543]. WDR5 broadly couples transcription factors to chromatin in development and cancer, partnering with Oct4 in pluripotency, C/EBPα p30 in AML, MYC and PTENα/β in tumor maintenance, and p53 in lineage gene control [PMID:21477851, PMID:26167872, PMID:31685992, PMID:31940490]. Its central cavity additionally discriminates histone modification context, reading H3Q5 serotonylation to promote H3K4me3 and being blocked by PRMT6-catalyzed H3R2me2a [PMID:34144982, PMID:32207970]. Beyond chromatin, WDR5 acts as a scaffold at the midbody to support cytokinetic abscission, at the mitotic spindle where it binds the Kif2A Win motif to regulate chromosome congression, and at replication origins to support MCM2-7 loading [PMID:25666610, PMID:28633016, PMID:27744293]. WDR5 is itself regulated post-translationally—phosphorylated by PAS kinase to drive H3K4me1→me3 conversion at differentiation promoters, methylated by SETD6, and ubiquitinated by FBXW7 for degradation during mitotic arrest [PMID:27661449, PMID:30226578, PMID:36395886]. WIN-site inhibitors kill MLL-rearranged and other cancer cells not by altering bulk methylation but by displacing WDR5 from ribosomal-protein gene loci, causing translational collapse, nucleolar stress, and p53 activation, motivating WDR5-targeting PROTAC degraders built on VHL and DCAF1 [PMID:30865883, PMID:31360909, PMID:38682900, PMID:34586829, PMID:39580491].","teleology":[{"year":2005,"claim":"Established WDR5 as an essential component coupling the MLL/SET1 machinery to the H3K4-methylated histone tail and to developmental gene expression, defining its core chromatin role.","evidence":"Co-IP and modified-peptide pull-downs plus RNAi knockdown with HOX/developmental readouts in Xenopus","pmids":["15960974"],"confidence":"High","gaps":["Did not resolve whether WDR5 reads methylation or presents the substrate","Molecular basis of recruitment to the complex unresolved"]},{"year":2006,"claim":"Resolved that WDR5 does not read K4 methylation state but presents the K4 side chain for further methylation, reframing its mechanistic function.","evidence":"High-resolution X-ray structures of WDR5 with unmodified/mono/di/tri-methylated H3K4 peptides","pmids":["16829959"],"confidence":"High","gaps":["Did not identify the true physiological ligand of the arginine pocket","Functional consequence in intact complexes not tested"]},{"year":2008,"claim":"Identified the MLL1 Win motif as the genuine ligand of the WDR5 arginine pocket, explaining how WDR5 nucleates core-complex assembly and catalytic activity.","evidence":"1.7 Å co-crystal structure of WDR5–MLL1 Win peptide plus ITC/fluorescence binding","pmids":["18829459"],"confidence":"High","gaps":["Generality across other SET1-family members untested at this stage","Win-motif partners outside MLL1 unknown"]},{"year":2011,"claim":"Extended WDR5 function to transcription-factor tethering and stem-cell control by linking it to Oct4 and pluripotency programs.","evidence":"Co-IP, genome-wide ChIP-seq, RNAi, and iPSC reprogramming assays","pmids":["21477851"],"confidence":"High","gaps":["Direct binding interface to Oct4 not mapped","Separation from histone-methylation role unresolved"]},{"year":2014,"claim":"Defined an RNA-binding pocket required for WDR5 chromatin occupancy and H3K4me3 maintenance independent of complex assembly, revealing a distinct functional surface.","evidence":"Structure-guided F266A mutagenesis, RIP, ChIP, RNA-seq, and ESC complementation","pmids":["24521543"],"confidence":"High","gaps":["Specific RNAs driving recruitment not mechanistically dissected","How RNA binding promotes chromatin retention unresolved"]},{"year":2014,"claim":"Showed WDR5 engagement is context-specific across complexes—joining NSL via KANSL motifs and restraining MLL3—establishing differential WDR5 dependence.","evidence":"X-ray structure of KANSL1/WDR5/KANSL2 subcomplex, mutagenesis in flies, and in vitro methyltransferase assays for MLL3","pmids":["24788516","26324722"],"confidence":"High","gaps":["Determinants selecting NSL vs MLL engagement in cells unclear","Mechanism by which WDR5 inhibits MLL3 not fully defined"]},{"year":2015,"claim":"Mapped the WBM site as a second binding surface that recruits MYC to chromatin genome-wide and is required for MYC-driven reprogramming and tumorigenesis.","evidence":"Co-IP, WDR5–MYC peptide co-crystal structure, ChIP-seq, structure-guided mutagenesis, iPSC and xenograft models","pmids":["25818646"],"confidence":"High","gaps":["Other WBM-site clients only partially enumerated","Whether MYC tethering requires intact MLL complex unclear"]},{"year":2016,"claim":"Systematized WDR5 as the universal Win-motif receptor for SET1-family complexes with graded functional importance, and demonstrated selective pharmacologic inhibition.","evidence":"In vitro reconstituted methyltransferase assays across all SET1-family members with mutagenesis and a ~3 nM peptidomimetic","pmids":["27563068"],"confidence":"High","gaps":["Cellular consequences of selective MLL1/SETd1A inhibition not detailed here","Basis for differential dependence across complexes unresolved"]},{"year":2017,"claim":"Revealed chromatin-independent scaffolding roles in mitosis, where WDR5 binds the Kif2A Win motif at the spindle and supports the midbody for abscission.","evidence":"Co-IP, Win-motif peptide binding, immunofluorescence, RNAi with mitotic phenotypes (spindle, congression, abscission)","pmids":["28633016","25666610"],"confidence":"Medium","gaps":["Single-lab findings without reciprocal cross-validation","Relationship between spindle and chromatin pools of WDR5 unclear"]},{"year":2019,"claim":"Reframed the therapeutic mechanism of WIN-site inhibitors as displacement of WDR5 from ribosomal-protein gene loci causing translational stress and p53 activation, not bulk methylation loss.","evidence":"Potent WIN-site inhibitor with ChIP-seq, RNA-seq, translational assays, and p53 pathway analysis in MLL-rearranged cells","pmids":["30865883","31360909"],"confidence":"High","gaps":["Locus selectivity determinants for displacement not fully defined","Generality beyond MLL-rearranged contexts established only later"]},{"year":2021,"claim":"Demonstrated that WDR5's central cavity discriminates histone modification context—reading H3Q5 serotonylation to promote H3K4me3—expanding its sensing repertoire.","evidence":"Crystal structures of WDR5–H3Q5ser/H3K4me3Q5ser complexes with ChIP-seq and neuroblastoma functional assays","pmids":["34144982","32207970"],"confidence":"High","gaps":["Physiological prevalence of H3Q5ser-directed WDR5 recruitment unclear","Interplay with R2 methylation switch in vivo untested"]},{"year":2021,"claim":"Established post-translational control of WDR5 itself via FBXW7-mediated ubiquitination and degradation during mitotic arrest, plus SETD6 methylation and PASK phosphorylation linking WDR5 turnover and activity to cell state.","evidence":"Co-IP, in vitro ubiquitination, kinase assay, mass-spec methylation mapping, and functional slippage/differentiation assays","pmids":["36395886","30226578","27661449"],"confidence":"Medium","gaps":["Cross-regulation among these PTMs not integrated","Single-lab biochemical reconstitutions for each modification"]},{"year":2024,"claim":"Refined the cancer-killing mechanism and advanced targeted degradation by linking WIN-site inhibition to MDM4 splicing-dependent p53 activation and developing VHL- and DCAF1-based WDR5 PROTACs.","evidence":"Multi-omics with splicing and drug-synergy analysis; ternary WDR5–PROTAC–VHL and –DCAF1 crystal structures with degradation assays","pmids":["38682900","34586829","39580491"],"confidence":"High","gaps":["Degrader efficacy across non-leukemic WDR5-dependent tumors not fully established","Selectivity of DCAF1 recruitment in cells incompletely characterized"]},{"year":null,"claim":"How WDR5's distinct functional surfaces (WIN, WBM, RNA pocket) are dynamically partitioned among chromatin, mitotic, mitochondrial, and ciliary roles within a single cell, and which roles dominate therapeutic responses, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model coordinating the multiple WDR5 surfaces in vivo","Relative contribution of chromatin-dependent vs -independent roles to phenotypes unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,11,15]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,28,31]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,18,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[21]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,4,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,17,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,30,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,11,35]}],"complexes":["MLL/SET1 (COMPASS) H3K4 methyltransferase complex","NSL complex","VISA antiviral signaling complex"],"partners":["MLL1","MYC","KIF2A","KANSL1","OCT4","P53","FBXW7","RBBP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61964","full_name":"WD repeat-containing protein 5","aliases":["BMP2-induced 3-kb gene protein"],"length_aa":334,"mass_kda":36.6,"function":"Contributes to histone modification (PubMed:16600877, PubMed:16829960, PubMed:19103755, PubMed:19131338, PubMed:19556245, PubMed:20018852). May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4' (PubMed:16829960). As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3 (PubMed:19556245). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:18840606). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:19103755, PubMed:20018852). May regulate osteoblasts differentiation (By similarity). In association with RBBP5 and ASH2L, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:21220120, PubMed:22266653)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P61964/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR5","classification":"Common Essential","n_dependent_lines":1185,"n_total_lines":1208,"dependency_fraction":0.9809602649006622},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":4.0},{"gene":"NUCKS1","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR5","total_profiled":1310},"omim":[{"mim_id":"621240","title":"WD REPEAT-CONTAINING PROTEIN 5B; WDR5B","url":"https://www.omim.org/entry/621240"},{"mim_id":"621221","title":"STX18 ANTISENSE RNA 1, NONCODING; STX18AS1","url":"https://www.omim.org/entry/621221"},{"mim_id":"618738","title":"TUBULIN TYROSINE LIGASE-LIKE 4; TTLL4","url":"https://www.omim.org/entry/618738"},{"mim_id":"618335","title":"LONG INTERGENIC NONCODING RNA 958; LINC00958","url":"https://www.omim.org/entry/618335"},{"mim_id":"617621","title":"PAX3- AND PAX7-BINDING PROTEIN 1; PAXBP1","url":"https://www.omim.org/entry/617621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR5"},"hgnc":{"alias_symbol":["SWD3","CFAP89","BIG-3"],"prev_symbol":[]},"alphafold":{"accession":"P61964","domains":[{"cath_id":"2.130.10.10","chopping":"35-330","consensus_level":"medium","plddt":98.1318,"start":35,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61964","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61964-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61964-F1-predicted_aligned_error_v6.png","plddt_mean":93.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR5","jax_strain_url":"https://www.jax.org/strain/search?query=WDR5"},"sequence":{"accession":"P61964","fasta_url":"https://rest.uniprot.org/uniprotkb/P61964.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61964/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61964"}},"corpus_meta":[{"pmid":"15960974","id":"PMC_15960974","title":"WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15960974","citation_count":670,"is_preprint":false},{"pmid":"21477851","id":"PMC_21477851","title":"Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21477851","citation_count":461,"is_preprint":false},{"pmid":"27147598","id":"PMC_27147598","title":"LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern.","date":"2016","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27147598","citation_count":336,"is_preprint":false},{"pmid":"25818646","id":"PMC_25818646","title":"Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25818646","citation_count":247,"is_preprint":false},{"pmid":"26167872","id":"PMC_26167872","title":"Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.","date":"2015","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/26167872","citation_count":242,"is_preprint":false},{"pmid":"21884981","id":"PMC_21884981","title":"Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21884981","citation_count":237,"is_preprint":false},{"pmid":"16829959","id":"PMC_16829959","title":"Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex.","date":"2006","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16829959","citation_count":212,"is_preprint":false},{"pmid":"24521543","id":"PMC_24521543","title":"Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24521543","citation_count":168,"is_preprint":false},{"pmid":"23210835","id":"PMC_23210835","title":"High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.","date":"2012","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/23210835","citation_count":167,"is_preprint":false},{"pmid":"28487115","id":"PMC_28487115","title":"lncRNA HOXD-AS1 Regulates Proliferation and Chemo-Resistance of Castration-Resistant Prostate Cancer via Recruiting WDR5.","date":"2017","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28487115","citation_count":160,"is_preprint":false},{"pmid":"18829459","id":"PMC_18829459","title":"Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18829459","citation_count":146,"is_preprint":false},{"pmid":"29385767","id":"PMC_29385767","title":"Moonlighting with WDR5: A Cellular Multitasker.","date":"2018","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29385767","citation_count":132,"is_preprint":false},{"pmid":"22989411","id":"PMC_22989411","title":"Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/22989411","citation_count":127,"is_preprint":false},{"pmid":"34586829","id":"PMC_34586829","title":"A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34586829","citation_count":114,"is_preprint":false},{"pmid":"28484075","id":"PMC_28484075","title":"TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28484075","citation_count":102,"is_preprint":false},{"pmid":"25656485","id":"PMC_25656485","title":"Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25656485","citation_count":102,"is_preprint":false},{"pmid":"24788516","id":"PMC_24788516","title":"Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex.","date":"2014","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/24788516","citation_count":99,"is_preprint":false},{"pmid":"30865883","id":"PMC_30865883","title":"Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30865883","citation_count":97,"is_preprint":false},{"pmid":"35280682","id":"PMC_35280682","title":"The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35280682","citation_count":94,"is_preprint":false},{"pmid":"35434944","id":"PMC_35434944","title":"HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program.","date":"2022","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35434944","citation_count":87,"is_preprint":false},{"pmid":"28603984","id":"PMC_28603984","title":"Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction.","date":"2017","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28603984","citation_count":85,"is_preprint":false},{"pmid":"20080758","id":"PMC_20080758","title":"WDR5 is essential for assembly of the VISA-associated signaling complex and virus-triggered IRF3 and NF-kappaB activation.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20080758","citation_count":83,"is_preprint":false},{"pmid":"27346354","id":"PMC_27346354","title":"Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27346354","citation_count":82,"is_preprint":false},{"pmid":"29987046","id":"PMC_29987046","title":"WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29987046","citation_count":79,"is_preprint":false},{"pmid":"34326167","id":"PMC_34326167","title":"WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape.","date":"2021","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34326167","citation_count":79,"is_preprint":false},{"pmid":"28300833","id":"PMC_28300833","title":"PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28300833","citation_count":78,"is_preprint":false},{"pmid":"32513988","id":"PMC_32513988","title":"LncRNA ANRIL acts as a modular scaffold of WDR5 and HDAC3 complexes and promotes alteration of the vascular smooth muscle cell phenotype.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32513988","citation_count":78,"is_preprint":false},{"pmid":"26958703","id":"PMC_26958703","title":"Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).","date":"2016","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26958703","citation_count":71,"is_preprint":false},{"pmid":"33601056","id":"PMC_33601056","title":"WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33601056","citation_count":68,"is_preprint":false},{"pmid":"30488017","id":"PMC_30488017","title":"The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer.","date":"2018","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30488017","citation_count":67,"is_preprint":false},{"pmid":"24051374","id":"PMC_24051374","title":"Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24051374","citation_count":67,"is_preprint":false},{"pmid":"31685992","id":"PMC_31685992","title":"PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31685992","citation_count":63,"is_preprint":false},{"pmid":"30205038","id":"PMC_30205038","title":"WDR5 Stabilizes Actin Architecture to Promote Multiciliated Cell Formation.","date":"2018","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/30205038","citation_count":62,"is_preprint":false},{"pmid":"28633016","id":"PMC_28633016","title":"MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/28633016","citation_count":61,"is_preprint":false},{"pmid":"26383167","id":"PMC_26383167","title":"The MYC-WDR5 Nexus and Cancer.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26383167","citation_count":60,"is_preprint":false},{"pmid":"27192115","id":"PMC_27192115","title":"WDR5 high expression and its effect on tumorigenesis in leukemia.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27192115","citation_count":59,"is_preprint":false},{"pmid":"27563068","id":"PMC_27563068","title":"Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27563068","citation_count":59,"is_preprint":false},{"pmid":"32223236","id":"PMC_32223236","title":"Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32223236","citation_count":54,"is_preprint":false},{"pmid":"36732025","id":"PMC_36732025","title":"WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.","date":"2023","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/36732025","citation_count":52,"is_preprint":false},{"pmid":"33980013","id":"PMC_33980013","title":"Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33980013","citation_count":51,"is_preprint":false},{"pmid":"31858797","id":"PMC_31858797","title":"Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31858797","citation_count":51,"is_preprint":false},{"pmid":"18201971","id":"PMC_18201971","title":"Wdr5 is essential for osteoblast differentiation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18201971","citation_count":50,"is_preprint":false},{"pmid":"31570196","id":"PMC_31570196","title":"Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex attenuates renal senescence in ischemia reperfusion mice by reduction of p16INK4a.","date":"2019","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/31570196","citation_count":46,"is_preprint":false},{"pmid":"34283608","id":"PMC_34283608","title":"Targeting WD Repeat-Containing Protein 5 (WDR5): A Medicinal Chemistry Perspective.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34283608","citation_count":45,"is_preprint":false},{"pmid":"30274785","id":"PMC_30274785","title":"lncRNA GCAWKR Promotes Gastric Cancer Development by Scaffolding the Chromatin Modification Factors WDR5 and KAT2A.","date":"2018","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30274785","citation_count":42,"is_preprint":false},{"pmid":"34144982","id":"PMC_34144982","title":"Structural insights into the recognition of histone H3Q5 serotonylation by WDR5.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34144982","citation_count":41,"is_preprint":false},{"pmid":"35525905","id":"PMC_35525905","title":"Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35525905","citation_count":41,"is_preprint":false},{"pmid":"16730692","id":"PMC_16730692","title":"Wdr5, a WD-40 protein, regulates osteoblast differentiation during embryonic bone development.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16730692","citation_count":41,"is_preprint":false},{"pmid":"29125890","id":"PMC_29125890","title":"Up-regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29125890","citation_count":38,"is_preprint":false},{"pmid":"29718303","id":"PMC_29718303","title":"The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29718303","citation_count":37,"is_preprint":false},{"pmid":"33022573","id":"PMC_33022573","title":"BPA modulates the WDR5/TET2 complex to regulate ERβ expression in eutopic endometrium and drives the development of endometriosis.","date":"2020","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/33022573","citation_count":37,"is_preprint":false},{"pmid":"29925347","id":"PMC_29925347","title":"WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage.","date":"2018","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29925347","citation_count":36,"is_preprint":false},{"pmid":"28229975","id":"PMC_28229975","title":"Diverse roles of WDR5-RbBP5-ASH2L-DPY30 (WRAD) complex in the functions of the SET1 histone methyltransferase family.","date":"2017","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/28229975","citation_count":35,"is_preprint":false},{"pmid":"29237839","id":"PMC_29237839","title":"Upon Infection, Cellular WD Repeat-Containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29237839","citation_count":31,"is_preprint":false},{"pmid":"32158922","id":"PMC_32158922","title":"Targeting MYC through WDR5.","date":"2020","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32158922","citation_count":30,"is_preprint":false},{"pmid":"31360909","id":"PMC_31360909","title":"Targeting WDR5: A WINning Anti-Cancer Strategy?","date":"2019","source":"Epigenetics insights","url":"https://pubmed.ncbi.nlm.nih.gov/31360909","citation_count":30,"is_preprint":false},{"pmid":"32067741","id":"PMC_32067741","title":"LncRNA HOTTIP enhances human osteogenic BMSCs differentiation via interaction with WDR5 and activation of Wnt/β-catenin signalling pathway.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32067741","citation_count":30,"is_preprint":false},{"pmid":"34105966","id":"PMC_34105966","title":"Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34105966","citation_count":30,"is_preprint":false},{"pmid":"25666610","id":"PMC_25666610","title":"WD repeat-containing protein 5 (WDR5) localizes to the midbody and regulates abscission.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25666610","citation_count":29,"is_preprint":false},{"pmid":"36594833","id":"PMC_36594833","title":"Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction.","date":"2023","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36594833","citation_count":28,"is_preprint":false},{"pmid":"30377171","id":"PMC_30377171","title":"WDR5 regulates left-right patterning via chromatin-dependent and -independent functions.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30377171","citation_count":28,"is_preprint":false},{"pmid":"31752957","id":"PMC_31752957","title":"WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells.","date":"2019","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/31752957","citation_count":28,"is_preprint":false},{"pmid":"30010961","id":"PMC_30010961","title":"H3K4me2 and WDR5 enriched chromatin interacting long non-coding RNAs maintain transcriptionally competent chromatin at divergent transcriptional units.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30010961","citation_count":26,"is_preprint":false},{"pmid":"32207970","id":"PMC_32207970","title":"A Binary Arginine Methylation Switch on Histone H3 Arginine 2 Regulates Its Interaction with WDR5.","date":"2020","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32207970","citation_count":26,"is_preprint":false},{"pmid":"39580491","id":"PMC_39580491","title":"Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39580491","citation_count":25,"is_preprint":false},{"pmid":"38019706","id":"PMC_38019706","title":"Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38019706","citation_count":24,"is_preprint":false},{"pmid":"31940490","id":"PMC_31940490","title":"p53 Integrates Temporal WDR5 Inputs during Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31940490","citation_count":24,"is_preprint":false},{"pmid":"29857126","id":"PMC_29857126","title":"Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29857126","citation_count":24,"is_preprint":false},{"pmid":"22523547","id":"PMC_22523547","title":"Synergistic effect of SRY and its direct target, WDR5, on Sox9 expression.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22523547","citation_count":23,"is_preprint":false},{"pmid":"14657013","id":"PMC_14657013","title":"BIG-3, a novel WD-40 repeat protein, is expressed in the developing growth plate and accelerates chondrocyte differentiation in vitro.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/14657013","citation_count":23,"is_preprint":false},{"pmid":"28528697","id":"PMC_28528697","title":"An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28528697","citation_count":23,"is_preprint":false},{"pmid":"26324722","id":"PMC_26324722","title":"Unique Role of the WD-40 Repeat Protein 5 (WDR5) Subunit within the Mixed Lineage Leukemia 3 (MLL3) Histone Methyltransferase Complex.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26324722","citation_count":23,"is_preprint":false},{"pmid":"34225179","id":"PMC_34225179","title":"Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity.","date":"2021","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34225179","citation_count":22,"is_preprint":false},{"pmid":"37021550","id":"PMC_37021550","title":"WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37021550","citation_count":21,"is_preprint":false},{"pmid":"31948749","id":"PMC_31948749","title":"WDR5-Myc axis promotes the progression of glioblastoma and neuroblastoma by transcriptional activating CARM1.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31948749","citation_count":20,"is_preprint":false},{"pmid":"29437978","id":"PMC_29437978","title":"WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29437978","citation_count":20,"is_preprint":false},{"pmid":"36207403","id":"PMC_36207403","title":"Discovery, evaluation and mechanism study of WDR5-targeted small molecular inhibitors for neuroblastoma.","date":"2022","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/36207403","citation_count":20,"is_preprint":false},{"pmid":"33977095","id":"PMC_33977095","title":"LncRNA-CCDC144NL-AS1 Promotes the Development of Hepatocellular Carcinoma by Inducing WDR5 Expression via Sponging miR-940.","date":"2021","source":"Journal of hepatocellular carcinoma","url":"https://pubmed.ncbi.nlm.nih.gov/33977095","citation_count":20,"is_preprint":false},{"pmid":"38682900","id":"PMC_38682900","title":"Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38682900","citation_count":19,"is_preprint":false},{"pmid":"36043466","id":"PMC_36043466","title":"Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36043466","citation_count":19,"is_preprint":false},{"pmid":"29130522","id":"PMC_29130522","title":"RhoJ promotes hypoxia induced endothelial-to-mesenchymal transition by activating WDR5 expression.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29130522","citation_count":19,"is_preprint":false},{"pmid":"38627584","id":"PMC_38627584","title":"The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38627584","citation_count":18,"is_preprint":false},{"pmid":"32345914","id":"PMC_32345914","title":"Inhibiting MLL1-WDR5 interaction ameliorates neuropathic allodynia by attenuating histone H3 lysine 4 trimethylation-dependent spinal mGluR5 transcription.","date":"2020","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/32345914","citation_count":18,"is_preprint":false},{"pmid":"33547232","id":"PMC_33547232","title":"Long Noncoding RNA NEAT1 Acts as a Molecular Switch for BRD4 Transcriptional Activity and Mediates Repression of BRD4/WDR5 Target Genes.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/33547232","citation_count":17,"is_preprint":false},{"pmid":"27661449","id":"PMC_27661449","title":"Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27661449","citation_count":17,"is_preprint":false},{"pmid":"35371306","id":"PMC_35371306","title":"DDX21 Interacts with WDR5 to Promote Colorectal Cancer Cell Proliferation by Activating CDK1 Expression.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35371306","citation_count":16,"is_preprint":false},{"pmid":"30880078","id":"PMC_30880078","title":"WDR5, BRCA1, and BARD1 Co-regulate the DNA Damage Response and Modulate the Mesenchymal-to-Epithelial Transition during Early Reprogramming.","date":"2019","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30880078","citation_count":15,"is_preprint":false},{"pmid":"35252869","id":"PMC_35252869","title":"Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells.","date":"2022","source":"NAR cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35252869","citation_count":14,"is_preprint":false},{"pmid":"31923859","id":"PMC_31923859","title":"Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction.","date":"2019","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31923859","citation_count":14,"is_preprint":false},{"pmid":"30703266","id":"PMC_30703266","title":"FOXD3 Suppresses Tumor-Initiating Features in Lung Cancer via Transcriptional Repression of WDR5.","date":"2019","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/30703266","citation_count":14,"is_preprint":false},{"pmid":"30226578","id":"PMC_30226578","title":"Lysines 207 and 325 methylation of WDR5 catalyzed by SETD6 promotes breast cancer cell proliferation and migration.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30226578","citation_count":14,"is_preprint":false},{"pmid":"30626558","id":"PMC_30626558","title":"The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening.","date":"2018","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/30626558","citation_count":14,"is_preprint":false},{"pmid":"34032265","id":"PMC_34032265","title":"Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions.","date":"2021","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/34032265","citation_count":14,"is_preprint":false},{"pmid":"37568727","id":"PMC_37568727","title":"Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37568727","citation_count":13,"is_preprint":false},{"pmid":"37307526","id":"PMC_37307526","title":"Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37307526","citation_count":13,"is_preprint":false},{"pmid":"19217897","id":"PMC_19217897","title":"Perichondrial expression of Wdr5 regulates chondrocyte proliferation and differentiation.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19217897","citation_count":13,"is_preprint":false},{"pmid":"28379447","id":"PMC_28379447","title":"WDR5 in porcine preimplantation embryos: expression, regulation of epigenetic modifications and requirement for early development†.","date":"2017","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/28379447","citation_count":13,"is_preprint":false},{"pmid":"36395886","id":"PMC_36395886","title":"The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36395886","citation_count":13,"is_preprint":false},{"pmid":"27744293","id":"PMC_27744293","title":"Regulation of DNA replication and chromosomal polyploidy by the MLL-WDR5-RBBP5 methyltransferases.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27744293","citation_count":12,"is_preprint":false},{"pmid":"37852994","id":"PMC_37852994","title":"MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1.","date":"2023","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/37852994","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48241,"output_tokens":10258,"usd":0.149296,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20797,"output_tokens":4871,"usd":0.11288,"stage2_stop_reason":"end_turn"},"total_usd":0.262176,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"WDR5 directly associates with histone H3 di- and trimethylated at K4 and with H3-K4-dimethylated nucleosomes. WDR5 is required for binding of the MLL1/MLL2/hSet1 methyltransferase complex to the K4-dimethylated H3 tail and for global H3K4 trimethylation. Depletion of WDR5 in X. laevis disrupts HOX gene expression and causes developmental defects.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays with modified histone peptides, RNAi knockdown in Xenopus, ChIP\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, in vivo knockdown with defined phenotypic readout, replicated across multiple labs subsequently\",\n      \"pmids\": [\"15960974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"High-resolution X-ray crystal structures of WDR5 alone and complexed with unmodified, mono-, di-, and trimethylated H3K4 peptides reveal that WDR5 does not read the methylation state of K4 directly; instead it presents the K4 side chain for further methylation by SET1-family complexes.\",\n      \"method\": \"X-ray crystallography (high-resolution structures), peptide binding assays\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with comprehensive methylation state analysis, foundational structural study replicated and cited widely\",\n      \"pmids\": [\"16829959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A conserved arginine-containing 'Win' motif in MLL1 (Arg-3765) binds into the same arginine-binding pocket on WDR5 that was previously suggested to bind histone H3. MLL1 Win peptide is preferentially recognized by WDR5, and this interaction is essential for MLL1 core complex assembly and H3K4 dimethylation activity.\",\n      \"method\": \"1.7 Å X-ray crystal structure of WDR5-MLL1 Win peptide complex, thermodynamic binding experiments (ITC/fluorescence)\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure plus thermodynamic binding data in single rigorous study\",\n      \"pmids\": [\"18829459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WDR5 is recruited to the mitochondrial outer membrane protein VISA in a viral-infection-dependent manner. Upon viral infection, WDR5 translocates from the nucleus to mitochondria and is essential for assembly of the VISA-associated signaling complex; knockdown of WDR5 impairs virus-triggered activation of IRF3 and NF-κB and reduces IFNB1 transcription.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, subcellular fractionation, siRNA knockdown with reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional knockdown in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20080758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR5 interacts with the pluripotency transcription factor Oct4 and overlapping genome-wide gene regulatory functions between Oct4 and WDR5 were demonstrated. WDR5 is required for ES cell self-renewal and efficient formation of induced pluripotent stem cells.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-seq, transcriptome analysis, RNAi knockdown, iPSC reprogramming assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genome-wide binding data and functional loss-of-function in multiple orthogonal assays\",\n      \"pmids\": [\"21477851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Under hypoxia, HDAC3 interacts with WDR5, recruits the histone methyltransferase complex to increase H3K4-specific HMT activity, and activates mesenchymal gene expression to promote EMT. Knockdown of WDR5 abolishes mesenchymal gene activation but not epithelial gene repression during hypoxia.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, H3K4 methyltransferase activity assay, gene expression analysis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, functional knockdown with specific phenotypic readout (mesenchymal vs epithelial gene regulation), single lab\",\n      \"pmids\": [\"21884981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Peptidomimetic inhibitors based on the MLL1 Win motif bind WDR5 with Ki < 1 nM and function as potent antagonists of MLL1 H3K4 methyltransferase activity in a fully reconstituted in vitro assay. Co-crystal structures of two peptidomimetics with WDR5 establish the structural basis for high-affinity binding.\",\n      \"method\": \"In vitro reconstituted H3K4 methyltransferase assay, co-crystal structures, binding affinity measurements, cell-based leukemia proliferation assays\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro enzymatic assay plus co-crystal structures with multiple compounds, rigorous mechanistic validation\",\n      \"pmids\": [\"23210835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Small-molecule antagonists of the WDR5 peptide-binding pocket (Win site) bind with Kd ~450 nM and inhibit the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations, consistent with WDR5 directly stabilizing the MLL multiprotein complex.\",\n      \"method\": \"Structural analysis, biophysical binding assays, in vitro H3K4 methyltransferase assay\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted enzymatic assay plus structural/biophysical characterization in single rigorous study\",\n      \"pmids\": [\"22989411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Glucagon/cAMP signaling causes dephosphorylation of CRTC2, which promotes recruitment of KAT2B and WDR5 to gluconeogenic gene promoters, increasing H3K9Ac and H3K4 methylation to activate hepatic gluconeogenesis. Depletion of WDR5 decreases gluconeogenic gene expression and blood glucose levels.\",\n      \"method\": \"Mouse models, in vitro chromatin assays, ChIP, siRNA knockdown, pharmacological inhibition\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, in vivo mouse models, and in vitro assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24051374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A specific RNA-binding pocket on WDR5 (mutated by F266A) selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. The F266A mutant cannot accumulate on chromatin, is defective in H3K4me3 maintenance and gene activation, and cannot sustain ESC self-renewal. A family of ESC mRNAs and lncRNAs interact with wild-type but not F266A WDR5, indicating RNA binding is required for WDR5 chromatin occupancy.\",\n      \"method\": \"Structure-guided mutagenesis, RNA immunoprecipitation, complementation assays in ESCs, ChIP, RNA-seq\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis distinguishing RNA-binding from complex assembly, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"24521543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WDR5 is recruited into the NSL (non-specific lethal) complex via conserved linear motifs of KANSL1 and KANSL2. Structural analysis shows the KANSL1/WDR5/KANSL2 subcomplex architecture. The KANSL1–WDR5 interaction is required for proper NSL complex assembly, efficient recruitment to target promoters, and fly viability. WDR5 interactions with NSL and MLL/COMPASS complexes are mutually exclusive.\",\n      \"method\": \"Structural analysis (X-ray crystallography), biochemical interaction mapping, structure-based KANSL1 mutants in transgenic flies, ChIP\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus structure-based mutagenesis with in vivo functional validation in Drosophila\",\n      \"pmids\": [\"24788516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYC binds WDR5 via an evolutionarily conserved 'MYC box IIIb' motif that engages a shallow hydrophobic cleft (WBM site) on WDR5. Structure-guided mutations disrupting this interaction attenuate MYC binding at ~80% of its chromosomal locations and disable MYC-driven iPSC formation and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, X-ray crystal structure of WDR5–MYC peptide complex, ChIP-seq, structure-guided mutagenesis, iPSC formation assay, xenograft tumor model\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus genome-wide ChIP-seq plus in vivo tumor model in single rigorous study\",\n      \"pmids\": [\"25818646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C/EBPα p30 (but not p42) isoform preferentially interacts with WDR5 in AML. p30-bound genomic regions are enriched for MLL-dependent H3K4me3. WDR5 downregulation inhibits p30-dependent cell proliferation and restores myeloid differentiation. OICR-9429, a small-molecule antagonist of the WDR5–MLL interaction, selectively inhibits proliferation and induces differentiation in p30-expressing AML cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, pharmacological inhibition with OICR-9429, differentiation assays\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, functional knockdown and pharmacological validation across multiple AML models\",\n      \"pmids\": [\"26167872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR5 localizes to the midbody and associates with PRC1 and CYK4/MKLP1. Knockdown of WDR5 impairs abscission, increases multinucleated cells, slows secondary ingression formation, and increases midbody microtubule resistance to depolymerization. Mutations disrupting the central arginine-binding cavity of WDR5 abolish midbody localization.\",\n      \"method\": \"Immunofluorescence localization, RNAi knockdown, live-cell imaging, microtubule depolymerization assays, mutagenesis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25666610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR5 has a unique role in the MLL3 complex: unlike MLL1, the MLL3 SET domain assembles with RbBP5/Ash2L independently of the Win motif–WDR5 interaction. WDR5 inhibits the monomethylation activity of the MLL3 core complex in a Win-motif-dependent manner. Solution structures by SAXS show similar overall topologies with or without WDR5.\",\n      \"method\": \"In vitro binding assays, in vitro methyltransferase activity assay, small-angle X-ray scattering (SAXS), mutagenesis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted enzymatic assay plus SAXS structures plus mutagenesis in single rigorous study\",\n      \"pmids\": [\"26324722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Win motif is necessary for interaction of WDR5 with all human SET1 family members. Mutation of the Win motif–WDR5 interface severely disrupts assembly and activity of MLL1 and SETd1A complexes but only modestly disrupts MLL2/4 and SETd1B complexes. For MLL3, WDR5 absence leads to enhanced monomethylation activity. A peptidomimetic (Kd ~3 nM) selectively inhibits MLL1 and SETd1A core complexes within the SET1 family.\",\n      \"method\": \"In vitro binding assays, in vitro H3K4 methyltransferase assays, mutagenesis, peptidomimetic inhibitor design\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro enzymatic assays across all SET1 family members with mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"27563068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cbx8 associates with non-PRC1 complexes containing WDR5. This Cbx8–WDR5 association maintains H3K4me3 levels on Notch-network gene promoters to regulate Notch signaling and promote mammary tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq for H3K4me3, RNAi knockdown, tumorsphere formation assay\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus ChIP-seq and functional assays, single lab\",\n      \"pmids\": [\"27346354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MLL/WDR5 complex localizes to the mitotic spindle apparatus. WDR5 directly interacts with Kif2A via a conserved Win motif in Kif2A, and this interaction regulates Kif2A localization to the spindle during mitosis. Loss of MLL/WDR5 function causes chromosome congression defects and compromised spindle formation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, in vitro binding assay with Win motif peptide\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated in vitro, localization shown by IF, functional loss-of-function with specific mitotic phenotype, single lab\",\n      \"pmids\": [\"28633016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TWIST1 forms a complex with WDR5 and the lncRNA Hottip. TWIST1 overexpression leads to co-enrichment of TWIST1 and WDR5 and increased H3K4me3 at the Hoxa9 promoter in a WDR5-dependent manner. WDR5 and Hottip expression are required for TWIST1-induced HOXA9 upregulation and invasive/migratory phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA/shRNA knockdown, cell invasion/migration assays, in vivo metastasis model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and functional knockdown with specific readouts, single lab\",\n      \"pmids\": [\"28484075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WIN site inhibitors displace WDR5 from chromatin at a specific cohort of loci enriched for ribosomal protein genes, causing decreased expression of associated genes, translational inhibition, nucleolar stress, and p53 induction.\",\n      \"method\": \"Potent WIN site inhibitor development, ChIP-seq, RNA-seq, translational assays, p53 pathway analysis\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus mechanistic pathway dissection with multiple functional readouts, replicated in subsequent studies\",\n      \"pmids\": [\"30865883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR5, independently of chromatin modification, regulates cell polarity, nuclear deformability, and migration of lymphocytes. Actomyosin contractility via MLCK-mediated myosin phosphorylation controls WDR5 interaction with other methyltransferase complex components, which in turn upregulates H3K4 methylation in 3D environments to reduce nuclear stiffness.\",\n      \"method\": \"Live imaging, FRAP, RNAi knockdown, atomic force microscopy, nuclear particle tracking, nuclear swelling experiments, pharmacological inhibition of MLCK\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biophysical measurements of nuclear mechanics, localization and functional consequences, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29987046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In multiciliated cells, WDR5 has a chromatin-independent scaffolding role: it binds to basal bodies, migrates apically, and F-actin organizes around WDR5. WDR5 stabilizes F-actin to maintain the apical lattice architecture required for basal body distribution and ciliogenesis.\",\n      \"method\": \"RNAi knockdown in Xenopus MCCs, live imaging, actin monomer trap (G-actin sequestration), immunofluorescence localization\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to basal bodies, functional consequence of knockdown, actin dynamics assay, single lab\",\n      \"pmids\": [\"30205038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR5 is recruited to cytoplasmic viral inclusion bodies of measles virus and is found in complexes containing viral RNA replication proteins. WDR5 deficiency decreases viral protein production and infectious virus yields, indicating WDR5 promotes viral replication.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, viral titer assays\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with viral proteins, direct localization to inclusion bodies, functional knockdown, single lab\",\n      \"pmids\": [\"29237839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD6 catalyzes monomethylation of WDR5 at lysines K207 and K325. Disrupting this methylation via K207R/K325R double mutation attenuates WDR5 promotion of breast cancer cell proliferation and migration, and partially reduces global H3K4me3 levels, without affecting MLL/SET1 complex assembly.\",\n      \"method\": \"Mass spectrometry identification of methylation sites, in vitro methyltransferase assay, site-directed mutagenesis, cell proliferation and migration assays, western blot for H3K4me3\",\n      \"journal\": \"Oncology Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus mutagenesis plus functional readout, single lab\",\n      \"pmids\": [\"30226578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR5 facilitates HCMV capsid nuclear egress: WDR5 knockdown impairs formation of the viral nuclear egress complex, reduces infoldings of the inner nuclear membrane, reduces capsid association with these infoldings, and decreases cytoplasmic capsids, resulting in dramatically reduced infectious virus titers.\",\n      \"method\": \"RNAi knockdown, transmission electron microscopy of nuclear membrane morphology, infectious titer assays, overexpression rescue\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific subcellular morphological phenotype and functional titer readout with knockdown and rescue, single lab\",\n      \"pmids\": [\"29437978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR5 localizes to the bases of cilia in the LR organizer and regulates foxj1 expression in monociliated cells. WDR5 has a dual role in left-right patterning: a chromatin/H3K4-dependent role in ciliogenesis via foxj1, and an H3K4-independent role revealed by a specific WDR5 mutant.\",\n      \"method\": \"WDR5 morpholino knockdown in Xenopus, rescue with foxj1, WDR5 H3K4-binding mutant analysis, immunofluorescence localization to cilia bases\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with genetic rescue, mutant analysis separating chromatin-dependent and independent roles, single lab\",\n      \"pmids\": [\"30377171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WIN site inhibitors kill MLL-rearranged cancer cells not through changes in histone methylation but by displacing WDR5 from chromatin at protein synthesis (ribosomal protein) genes, causing translational inhibition and p53 induction via nucleolar stress.\",\n      \"method\": \"ChIP-seq, RNA-seq, translational reporters, p53 pathway analysis, pharmacological WIN site inhibitors\",\n      \"journal\": \"Epigenetics Insights\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established with genome-wide data and multiple assays, single lab (consistent with independent Cell Reports 2019 paper)\",\n      \"pmids\": [\"31360909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTENα and PTENβ directly interact with WDR5 to promote H3K4 trimethylation and maintain a tumor-promoting transcriptional signature. USP9X deubiquitinates and FBXW11 ubiquitinates PTENα at K235/K239 to regulate PTENα/β stability, which in turn controls WDR5-dependent H3K4me3.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, ubiquitination assays, in vitro binding assays, knockdown/overexpression\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP-seq with functional pathway placement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31685992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3R2 arginine methylation acts as a binary switch regulating WDR5 interaction: H3R2me2a (PRMT6-catalyzed) prevents WDR5 binding, whereas H3R2me0, -me1, and -me2s (PRMT5-catalyzed) are equally permissive for WDR5 interaction. Crystal structures of WDR5 with unmodified and methylated arginine/H3R2 peptides provide structural basis for this selectivity.\",\n      \"method\": \"Quantitative binding analysis, X-ray crystal structures of WDR5 with me0/me1/me2s arginine and H3R2me1 peptide\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures combined with quantitative binding assays, rigorous biochemical characterization of methylation-state discrimination\",\n      \"pmids\": [\"32207970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR5 directly interacts with p53, enabling their co-recruitment to and regulation of genes controlling cell proliferation and fate. In mESCs, WDR5 binds to and activates neural genes via an RbBP5-dependent process; after prolonged inhibition and rescue, WDR5 targets mesoderm lineage genes in a p53-dependent fashion.\",\n      \"method\": \"Co-immunoprecipitation of WDR5–p53, ChIP-seq, ATAC-seq, Wdr5 conditional knockout and rescue in mESCs\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genome-wide chromatin assays and genetic rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31940490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAS kinase (Pask) phosphorylates Wdr5 to regulate myoblast differentiation. Pask stimulates conversion of repressive H3K4me1 to activating H3K4me3 on the Myog promoter via Wdr5 phosphorylation, enhancing MyoD accessibility and transcriptional activation of myogenin to initiate muscle differentiation.\",\n      \"method\": \"In vitro kinase assay (Pask phosphorylates Wdr5), ChIP for H3K4me1/me3, genetic knockdown/knockout in myoblasts, Myog promoter activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus ChIP plus functional differentiation assays, single lab\",\n      \"pmids\": [\"27661449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR5 functions as a 'reader' for histone H3Q5 serotonylation (H3Q5ser). Crystal structures of WDR5 complexed with H3Q5ser and H3K4me3Q5ser peptides show the serotonyl group accommodated in a shallow surface pocket. WDR5 recognition of H3Q5ser promotes H3K4me3 deposition; disruption of this interaction impairs H3K4me3 and reduces expression of cancer-promoting genes in neuroblastoma cells.\",\n      \"method\": \"X-ray crystallography (WDR5–H3Q5ser and –H3K4me3Q5ser complexes), binding assays, ChIP-seq, cell-based functional assays in neuroblastoma cells\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus functional validation in cells with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34144982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR5 is a substrate of the SCF-FBXW7 E3 ubiquitin ligase. WDR5 interacts with FBXW7 in vivo and in vitro; FBXW7 mediates WDR5 ubiquitination and proteasomal degradation during prolonged mitotic arrest. WDR5 depletion reduces mitotic slippage, establishing WDR5 as a pro-slippage factor downstream of FBXW7.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, in vitro ubiquitination assay, proteasome inhibitor experiments, RNAi knockdown\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitination reconstitution plus Co-IP plus functional slippage assay, single lab\",\n      \"pmids\": [\"36395886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A selective WDR5 degrader (MS67) designed via crystal structures of WDR5–degrader–VHL ternary complexes potently depletes WDR5, decreases chromatin-bound MLL complex components and c-MYC, suppresses WDR5-regulated gene transcription more effectively than PPI inhibitors, and inhibits MLL-rearranged AML patient cell growth in vivo.\",\n      \"method\": \"Crystal structures of ternary WDR5–PROTAC–VHL complexes, biophysical cooperativity measurements, ChIP, RNA-seq, in vitro and in vivo AML patient-derived models\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures of ternary complexes plus in vitro and in vivo functional validation with multiple orthogonal methods\",\n      \"pmids\": [\"34586829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR5 promotes cell growth in breast cancer by increasing ribosomal gene expression and translation efficiency in a KMT2 (MLL)-independent manner. Pharmacological inhibition or degradation of WDR5 impedes cellular translation rate; combination with mTOR inhibitors potently suppresses translation and proliferation.\",\n      \"method\": \"In vivo genetic screen, RNAi knockdown, ribosome profiling/translation efficiency assays, pharmacological inhibitor/degrader treatment, mTOR inhibitor combination studies\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo screen plus mechanistic translational assays, KMT2-independence established, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36043466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WDR5 is required for DUX4 expression in FSHD muscle cells through its interaction with the lncRNA DBE-T (identified by affinity purification/proteomics). WDR5 inhibition/knockdown rescues cell viability and myogenic differentiation of FSHD patient cells without harming healthy donor cells.\",\n      \"method\": \"Affinity purification + proteomics (DBE-T interactors), RNAi knockdown, pharmacological WDR5 inhibition, differentiation assays in primary FSHD muscle cells\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification/proteomics for interaction identification plus functional knockdown and pharmacological validation, single lab\",\n      \"pmids\": [\"37021550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR5 WIN site inhibition in MLL-rearranged leukemia cells suppresses ribosome protein gene (RPG) transcription, causes ribosome depletion and a broad translational choke, and inactivates the p53 antagonist MDM4 through changes in alternative mRNA splicing, activating p53 and killing cancer cells. WIN site inhibitors are synergistic with venetoclax and BET-bromodomain inhibitors.\",\n      \"method\": \"Multi-omics (ChIP-seq, RNA-seq, ribosome profiling, proteomics), alternative splicing analysis, drug synergy assays in MLL-rearranged cell lines\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated multi-omics approach with multiple orthogonal methods delineating mechanism, synergy with orthogonal drugs, consistent with prior Cell Reports 2019 findings\",\n      \"pmids\": [\"38682900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structures of DCAF1–PROTAC–WDR5 ternary complexes reveal that DCAF1 loops provide surface plasticity enabling recruitment of WDR5 as a substrate for DCAF1-containing CUL4 E3 ligases. Four DCAF1-based PROTACs achieve WDR5 degradation, with the ternary structures informing substrate specificity of DCAF1.\",\n      \"method\": \"High-resolution X-ray crystal structures of ternary DCAF1–PROTAC–WDR5 complexes, WDR5 degradation assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures of ternary complexes with functional degradation validation in single rigorous study\",\n      \"pmids\": [\"39580491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WDR5 (originally identified as BIG-3, a BMP-2-induced gene) is expressed in proliferating and hypertrophic chondrocytes in the developing growth plate and accelerates chondrocyte differentiation in vitro when stably overexpressed, increasing matrix proteoglycan synthesis, alkaline phosphatase, osteopontin, and mineralized matrix formation.\",\n      \"method\": \"Stable transfection/overexpression in chondrogenic ATDC5 cells, biochemical differentiation markers, BMP-2 treatment\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function with multiple differentiation readouts in single lab; foundational identification paper for BIG-3/WDR5 in chondrocytes\",\n      \"pmids\": [\"14657013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WDR5 knockdown in MC3T3-E1 osteoblasts markedly inhibits osteoblast differentiation (reduced alkaline phosphatase, Runx-2, osteocalcin, mineralized matrix), reduces H3K4me3, and disrupts the canonical Wnt signaling pathway by decreasing Wnt expression and nuclear β-catenin. ChIP demonstrates WDR5 occupancy at the Wnt1 promoter and canonical Wnt response elements on c-myc and Runx-2 promoters.\",\n      \"method\": \"Stable siRNA knockdown, alkaline phosphatase assay, mineralization assay, qPCR, western blot, ChIP\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple differentiation readouts plus ChIP for direct promoter occupancy, single lab\",\n      \"pmids\": [\"18201971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Regulation of DNA replication: WDR5 (as part of MLL–WDR5–RBBP5 complex) co-localizes with ORC and MCM2-7 at replication origins. WDR5 or RBBP5 knockdown suppresses DNA re-replication and chromosomal polyploidy, reduces H3K4me at origins, and suppresses MCM2-7 recruitment to origins.\",\n      \"method\": \"siRNA knockdown, ChIP at replication origins, flow cytometry for polyploidy, H2AX checkpoint assays\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at replication origins plus functional replication and polyploidy assays with knockdown, single lab\",\n      \"pmids\": [\"27744293\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR5 is a WD40-repeat scaffold protein that operates at multiple levels of chromatin regulation and beyond: its central arginine-binding cavity (WIN site) recruits WDR5 to all SET1/MLL family histone H3K4 methyltransferase complexes by engaging a conserved Win motif in catalytic subunits, positioning the K4 side chain for methylation rather than reading the methylation state directly; a distinct surface pocket (WBM site) mediates direct interaction with MYC and other transcription factors to tether them to chromatin; a separate RNA-binding pocket is required for WDR5 chromatin accumulation and H3K4me3 maintenance; and WDR5 additionally reads H3Q5 serotonylation and H3R2 methylation status via its central cavity. Beyond chromatin, WDR5 localizes to the midbody to promote cytokinetic abscission, to the mitotic spindle to regulate Kif2A-dependent chromosome congestion, to basal bodies in multiciliated cells to stabilize F-actin architecture, to mitochondria during viral infection to assemble the VISA antiviral signaling complex, and to replication origins to support MCM loading. WDR5 is itself regulated post-translationally by SETD6-mediated lysine methylation (K207/K325) and FBXW7-mediated ubiquitination and proteasomal degradation during mitotic arrest, while upstream kinase PASK phosphorylates WDR5 to drive H3K4me1→me3 conversion at differentiation gene promoters.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR5 is a WD40-repeat scaffold protein that organizes histone H3K4 methylation by the SET1/MLL family of methyltransferases and tethers these and other transcriptional regulators to chromatin [#0, #15]. Rather than reading the K4 methylation state, WDR5 presents the H3K4 side chain for catalysis, and its central arginine-binding cavity (the WIN site) instead engages a conserved arginine-containing Win motif in the catalytic subunits—first defined for MLL1—to drive core-complex assembly and H3K4 dimethylation [#1, #2]. The Win motif is required for WDR5 association with all human SET1-family members, though WDR5 dependence varies by complex: it is critical for MLL1 and SETd1A but only modestly required for MLL2/4 and SETd1B, and it restrains rather than promotes MLL3 monomethylation activity [#15, #14]. WDR5 also recruits MYC to ~80% of its chromosomal sites through a distinct shallow hydrophobic cleft (the WBM site) that binds the MYC box IIIb motif, and is incorporated into the NSL complex via KANSL1/KANSL2 linear motifs in a manner mutually exclusive with MLL/COMPASS engagement [#11, #10]. A separate RNA-binding pocket is required for WDR5 chromatin accumulation, H3K4me3 maintenance, and ESC self-renewal independently of complex assembly [#9]. WDR5 broadly couples transcription factors to chromatin in development and cancer, partnering with Oct4 in pluripotency, C/EBPα p30 in AML, MYC and PTENα/β in tumor maintenance, and p53 in lineage gene control [#4, #12, #27, #29]. Its central cavity additionally discriminates histone modification context, reading H3Q5 serotonylation to promote H3K4me3 and being blocked by PRMT6-catalyzed H3R2me2a [#31, #28]. Beyond chromatin, WDR5 acts as a scaffold at the midbody to support cytokinetic abscission, at the mitotic spindle where it binds the Kif2A Win motif to regulate chromosome congression, and at replication origins to support MCM2-7 loading [#13, #17, #40]. WDR5 is itself regulated post-translationally—phosphorylated by PAS kinase to drive H3K4me1→me3 conversion at differentiation promoters, methylated by SETD6, and ubiquitinated by FBXW7 for degradation during mitotic arrest [#30, #23, #32]. WIN-site inhibitors kill MLL-rearranged and other cancer cells not by altering bulk methylation but by displacing WDR5 from ribosomal-protein gene loci, causing translational collapse, nucleolar stress, and p53 activation, motivating WDR5-targeting PROTAC degraders built on VHL and DCAF1 [#19, #26, #36, #33, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established WDR5 as an essential component coupling the MLL/SET1 machinery to the H3K4-methylated histone tail and to developmental gene expression, defining its core chromatin role.\",\n      \"evidence\": \"Co-IP and modified-peptide pull-downs plus RNAi knockdown with HOX/developmental readouts in Xenopus\",\n      \"pmids\": [\"15960974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether WDR5 reads methylation or presents the substrate\", \"Molecular basis of recruitment to the complex unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved that WDR5 does not read K4 methylation state but presents the K4 side chain for further methylation, reframing its mechanistic function.\",\n      \"evidence\": \"High-resolution X-ray structures of WDR5 with unmodified/mono/di/tri-methylated H3K4 peptides\",\n      \"pmids\": [\"16829959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the true physiological ligand of the arginine pocket\", \"Functional consequence in intact complexes not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the MLL1 Win motif as the genuine ligand of the WDR5 arginine pocket, explaining how WDR5 nucleates core-complex assembly and catalytic activity.\",\n      \"evidence\": \"1.7 Å co-crystal structure of WDR5–MLL1 Win peptide plus ITC/fluorescence binding\",\n      \"pmids\": [\"18829459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across other SET1-family members untested at this stage\", \"Win-motif partners outside MLL1 unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended WDR5 function to transcription-factor tethering and stem-cell control by linking it to Oct4 and pluripotency programs.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP-seq, RNAi, and iPSC reprogramming assays\",\n      \"pmids\": [\"21477851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface to Oct4 not mapped\", \"Separation from histone-methylation role unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined an RNA-binding pocket required for WDR5 chromatin occupancy and H3K4me3 maintenance independent of complex assembly, revealing a distinct functional surface.\",\n      \"evidence\": \"Structure-guided F266A mutagenesis, RIP, ChIP, RNA-seq, and ESC complementation\",\n      \"pmids\": [\"24521543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific RNAs driving recruitment not mechanistically dissected\", \"How RNA binding promotes chromatin retention unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed WDR5 engagement is context-specific across complexes—joining NSL via KANSL motifs and restraining MLL3—establishing differential WDR5 dependence.\",\n      \"evidence\": \"X-ray structure of KANSL1/WDR5/KANSL2 subcomplex, mutagenesis in flies, and in vitro methyltransferase assays for MLL3\",\n      \"pmids\": [\"24788516\", \"26324722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting NSL vs MLL engagement in cells unclear\", \"Mechanism by which WDR5 inhibits MLL3 not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the WBM site as a second binding surface that recruits MYC to chromatin genome-wide and is required for MYC-driven reprogramming and tumorigenesis.\",\n      \"evidence\": \"Co-IP, WDR5–MYC peptide co-crystal structure, ChIP-seq, structure-guided mutagenesis, iPSC and xenograft models\",\n      \"pmids\": [\"25818646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other WBM-site clients only partially enumerated\", \"Whether MYC tethering requires intact MLL complex unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Systematized WDR5 as the universal Win-motif receptor for SET1-family complexes with graded functional importance, and demonstrated selective pharmacologic inhibition.\",\n      \"evidence\": \"In vitro reconstituted methyltransferase assays across all SET1-family members with mutagenesis and a ~3 nM peptidomimetic\",\n      \"pmids\": [\"27563068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences of selective MLL1/SETd1A inhibition not detailed here\", \"Basis for differential dependence across complexes unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed chromatin-independent scaffolding roles in mitosis, where WDR5 binds the Kif2A Win motif at the spindle and supports the midbody for abscission.\",\n      \"evidence\": \"Co-IP, Win-motif peptide binding, immunofluorescence, RNAi with mitotic phenotypes (spindle, congression, abscission)\",\n      \"pmids\": [\"28633016\", \"25666610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without reciprocal cross-validation\", \"Relationship between spindle and chromatin pools of WDR5 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reframed the therapeutic mechanism of WIN-site inhibitors as displacement of WDR5 from ribosomal-protein gene loci causing translational stress and p53 activation, not bulk methylation loss.\",\n      \"evidence\": \"Potent WIN-site inhibitor with ChIP-seq, RNA-seq, translational assays, and p53 pathway analysis in MLL-rearranged cells\",\n      \"pmids\": [\"30865883\", \"31360909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Locus selectivity determinants for displacement not fully defined\", \"Generality beyond MLL-rearranged contexts established only later\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that WDR5's central cavity discriminates histone modification context—reading H3Q5 serotonylation to promote H3K4me3—expanding its sensing repertoire.\",\n      \"evidence\": \"Crystal structures of WDR5–H3Q5ser/H3K4me3Q5ser complexes with ChIP-seq and neuroblastoma functional assays\",\n      \"pmids\": [\"34144982\", \"32207970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological prevalence of H3Q5ser-directed WDR5 recruitment unclear\", \"Interplay with R2 methylation switch in vivo untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-translational control of WDR5 itself via FBXW7-mediated ubiquitination and degradation during mitotic arrest, plus SETD6 methylation and PASK phosphorylation linking WDR5 turnover and activity to cell state.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, kinase assay, mass-spec methylation mapping, and functional slippage/differentiation assays\",\n      \"pmids\": [\"36395886\", \"30226578\", \"27661449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-regulation among these PTMs not integrated\", \"Single-lab biochemical reconstitutions for each modification\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the cancer-killing mechanism and advanced targeted degradation by linking WIN-site inhibition to MDM4 splicing-dependent p53 activation and developing VHL- and DCAF1-based WDR5 PROTACs.\",\n      \"evidence\": \"Multi-omics with splicing and drug-synergy analysis; ternary WDR5–PROTAC–VHL and –DCAF1 crystal structures with degradation assays\",\n      \"pmids\": [\"38682900\", \"34586829\", \"39580491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degrader efficacy across non-leukemic WDR5-dependent tumors not fully established\", \"Selectivity of DCAF1 recruitment in cells incompletely characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR5's distinct functional surfaces (WIN, WBM, RNA pocket) are dynamically partitioned among chromatin, mitotic, mitochondrial, and ciliary roles within a single cell, and which roles dominate therapeutic responses, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model coordinating the multiple WDR5 surfaces in vivo\", \"Relative contribution of chromatin-dependent vs -independent roles to phenotypes unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 11, 15]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 28, 31]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 18, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 4, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 17, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 30, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 11, 35]}\n    ],\n    \"complexes\": [\"MLL/SET1 (COMPASS) H3K4 methyltransferase complex\", \"NSL complex\", \"VISA antiviral signaling complex\"],\n    \"partners\": [\"MLL1\", \"MYC\", \"Kif2A\", \"KANSL1\", \"Oct4\", \"p53\", \"FBXW7\", \"RbBP5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":10,"faith_pct":90.0}}