{"gene":"RBBP7","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1998,"finding":"RbAp46 (RBBP7) and RbAp48 are components of the NuRD multisubunit complex, which contains both ATP-dependent nucleosome remodeling and histone deacetylase (HDAC1/2) activities; RbAp46/48 form a core histone deacetylase complex shared between NuRD and Sin3-HDAC complexes, and MTA2 modulates the enzymatic activity of this core complex.","method":"Biochemical purification, co-immunoprecipitation, mass spectrometry identification of complex subunits","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution of complex, replicated across multiple labs (Zhang 1998, Xue 1998, Tong 1998, Wade 1999)","pmids":["10444591","9885572","9804427","9790534"],"is_preprint":false},{"year":1997,"finding":"RbAp46/RbAp48 (RBBP7/RBBP4) are histone-binding proteins that tether the mSin3 co-repressor complex (containing HDAC1 and HDAC2) to core histone proteins, enabling transcriptional repression.","method":"Biochemical purification, co-immunoprecipitation, functional transcription repression assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — biochemical complex reconstitution, replicated","pmids":["9150135"],"is_preprint":false},{"year":1999,"finding":"RbAp46/48 are subunits of the Mi-2/NuRD complex in Xenopus and human cells, which couples DNA methylation to histone deacetylation and chromatin remodeling; MBD2 directs the complex to methylated DNA.","method":"Biochemical purification from Xenopus egg extracts and human cell lines, subunit identification by mass spectrometry and cloning","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution across species, replicated by multiple labs","pmids":["10471499","10471500"],"is_preprint":false},{"year":1998,"finding":"RbAp46 (RBBP7) is transcriptionally induced ~15-fold by the Wilms' tumor suppressor WT1, and its overexpression inhibits cell growth and colony formation, identifying it as a mediator of WT1-dependent growth inhibition.","method":"Suppression subtractive hybridization PCR to identify WT1 target genes; colony formation and growth rate assays in transfected cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — gene expression induction confirmed, functional readout (colony formation, growth rate) with mechanistic link to WT1","pmids":["9765217"],"is_preprint":false},{"year":2001,"finding":"RbAp46 (RBBP7) interacts specifically with the BRCT domain of BRCA1 via its first two WD-repeat domains, and represses BRCA1-mediated transactivation of the p21 promoter; this interaction is disrupted by DNA-damaging agents.","method":"Yeast two-hybrid screening, co-immunoprecipitation, luciferase transactivation assay, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding confirmed, functional transactivation assay, DNA damage disruption shown","pmids":["11394910"],"is_preprint":false},{"year":2001,"finding":"RbAp46 (RBBP7) overexpression suppresses clonal growth of HEK293 cells in soft agar, inhibits tumor growth in nude mice, increases the G2/M cell fraction, and augments apoptosis in serum-starved cells.","method":"Soft agar colony formation, nude mouse xenograft, cell cycle analysis (flow cytometry), apoptosis assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional readouts in same study","pmids":["11433396"],"is_preprint":false},{"year":2002,"finding":"RbAp46/RbAp48 (RBBP7/RBBP4) are components of the PRC2 (Polycomb repressive complex 2), which contains Enhancer of Zeste, Extra sex combs, and Su(z)12, and possesses histone methyltransferase activity specific for H3K9 and H3K27; the HMT activity requires an intact SET domain in E(z).","method":"Biochemical purification, co-immunoprecipitation, histone methyltransferase assay, domain mutagenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — in vitro HMT assay with mutagenesis, replicated","pmids":["12435631"],"is_preprint":false},{"year":2003,"finding":"RbAp46 (RBBP7) inducible expression activates the c-Jun NH2-terminal kinase (JNK) pathway and triggers apoptosis; a dominant-negative JNK1 mutant blocks RbAp46-mediated apoptosis, placing RbAp46 upstream of JNK in a pro-apoptotic pathway.","method":"Tetracycline-inducible expression system, JNK kinase assay, dominant-negative JNK1 epistasis, xenograft tumor model","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with dominant-negative mutant establishes pathway position","pmids":["14981905"],"is_preprint":false},{"year":2004,"finding":"The Drosophila ortholog of RbAp46/48, p55/dCAF-1, is essential for repression of dE2F2-regulated target genes by RBF1 and RBF2 complexes; RNAi depletion of p55 specifically deregulates cell cycle-independent E2F2 targets without affecting proliferation-coupled E2F1 targets, revealing mechanistically distinct repression pathways.","method":"RNAi depletion in Drosophila cells, RT-PCR of E2F target genes, genetic epistasis analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — RNAi loss-of-function with specific target gene readouts, epistasis distinguishing two repression pathways","pmids":["15456884"],"is_preprint":false},{"year":2006,"finding":"RbAp46 (RBBP7) expression in mammary epithelial cells increases GSK-3β expression, leading to hyperphosphorylation and reduced steady-state levels of β-catenin, thereby suppressing β-catenin/TCF nuclear signaling and cell growth.","method":"Stable transfection, Western blot, luciferase reporter assay for β-catenin/TCF signaling","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Western blot + reporter assay, pathway placement indirect","pmids":["17201172"],"is_preprint":false},{"year":2008,"finding":"SUMO-1 forms a protein complex with RbAp46 (RBBP7) in the nucleus (co-localization and co-immunoprecipitation), stabilizing RbAp46 protein levels post-translationally without sumoylating RbAp46 directly; SUMO-1-mediated stabilization of RbAp46 enhances suppression of Ras-induced cell proliferation.","method":"Co-immunoprecipitation, co-localization imaging, Western blot, cell growth assays","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single Co-IP method; mechanism of stabilization not fully resolved","pmids":["19189660"],"is_preprint":false},{"year":2013,"finding":"RBBP7 is a dormant maternal mRNA recruited for translation during mouse oocyte maturation to regulate histone deacetylation; RBBP7 depletion by siRNA/morpholino impairs maturation-associated histone deacetylation, which in turn is required for chromosomal passenger complex (CPC) localization and function, causing chromosome misalignment, improper kinetochore-microtubule attachments, impaired spindle assembly checkpoint, cytokinesis defects, and increased aneuploidy at metaphase II.","method":"siRNA/morpholino knockdown, immunofluorescence of CPC components, histone acetylation assays, chromosome segregation analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts linking RBBP7 to histone deacetylation and CPC function","pmids":["24317350"],"is_preprint":false},{"year":2015,"finding":"RBBP7 acts as a substrate-specific adaptor (DCAF) in the CRL4 (CUL4-DDB1-ROC1) E3 ubiquitin ligase complex; CRL4(RBBP7) is required for ubiquitin-dependent loading of newly synthesized CENP-A at centromeres during G1, and RBBP7 also stabilizes soluble pre-nucleosomal CENP-A.","method":"RNAi depletion, quantitative imaging of CENP-A dynamics, biochemical co-immunoprecipitation, cell cycle staging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — biochemical and imaging methods combined, specific CRL4 adaptor function demonstrated","pmids":["25795299"],"is_preprint":false},{"year":2015,"finding":"Rbbp7 expression in mouse uterine stromal cells is induced by progesterone-nuclear receptor PR signaling; siRNA knockdown of Rbbp7 in primary murine stromal cells compromises decidualization by attenuating histone H4 acetylation and cyclin D3 expression.","method":"In situ hybridization, immunochemistry, siRNA knockdown, in vitro decidualization model, histone acetylation assay, Western blot","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific epigenetic and cell-differentiation readouts","pmids":["26040671"],"is_preprint":false},{"year":2015,"finding":"RbAp46 (RBBP7) is upregulated by oncogenic Ha-ras and forms a complex with HDAC1 and Sp1 that binds the RECK promoter at Sp1 sites, repressing RECK expression and thereby increasing MMP-9 activity and promoting lung metastasis in vivo.","method":"Suppression subtractive hybridization PCR, ChIP assay, DNA affinity precipitation, RECK reporter gene assay, shRNA knockdown, xenograft nude mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (ChIP, DAPA, reporter assay) with in vivo validation","pmids":["25885317"],"is_preprint":false},{"year":2016,"finding":"RbAp46/48 (LIN-53), the C. elegans ortholog of RBBP7, is required for CENP-A(HCP-3) localization at holocentromeres; its centromeric localization during metaphase is interdependent with CENP-A and depends on M18BP1(KNL-2); depletion causes anaphase bridges and chromosome missegregation, and this function is independent of histone acetylation, H3K27 trimethylation, or known chromatin-modifying complexes.","method":"RNAi depletion in C. elegans, immunofluorescence of centromere/kinetochore proteins, epistasis analysis with KNL-2 and CENP-A","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — epistasis analysis with multiple centromere components, orthogonal imaging and genetic methods","pmids":["26904949"],"is_preprint":false},{"year":2017,"finding":"AMPK directly phosphorylates RBBP7 at consensus phosphorylation sequences; AMPK-mediated phosphorylation of RBBP7 increases its interaction with and inhibition of DNMT1, contributing to reduced DNA methylation and increased expression of mitochondrial biogenesis genes (PGC-1α, Tfam, UCP2, UCP3).","method":"Consensus sequence analysis, biochemical phosphorylation assays, co-immunoprecipitation, pharmacological AMPK activation, pulsatile shear stress in HUVECs, mouse aorta studies with AMPKα2 knockout","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — direct phosphorylation demonstrated biochemically, functional consequence confirmed in cells and in vivo with genetic controls","pmids":["28143904"],"is_preprint":false},{"year":2017,"finding":"The human MTA2-RBBP7 sub-complex of NuRD can be isolated as a stable entity; negative stain electron microscopy reveals an elongated architecture capable of hinge-like motion, with stoichiometry analogous to the Drosophila NuRD MTA-RBBP complex (2:4 MTA:RBBP), suggesting MTA-RBBP is a stable core module for NuRD assembly.","method":"HEK293F cell expression, biochemical purification, negative stain electron microscopy, 3D reconstruction","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Medium","confidence_rationale":"Tier 1 — structural EM with purified complex; single study without higher-resolution validation","pmids":["28179136"],"is_preprint":false},{"year":2018,"finding":"RBBP7 is the substrate-receptor (DCAF) in the CRL4B E3 ubiquitin ligase complex (CRL4B-RBBP7) that bridges DDB1-CUL4B-ROC1 to HUWE1, mediating HUWE1 polyubiquitination and proteasomal degradation; RBBP7 overexpression promotes HUWE1 degradation, while RBBP7 depletion stabilizes HUWE1 and accelerates degradation of MCL-1 and BRCA1.","method":"Co-immunoprecipitation, overexpression/depletion experiments, ubiquitination assay, Western blot for substrate levels","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function experiments, ubiquitination assay; single lab","pmids":["29738775"],"is_preprint":false},{"year":2021,"finding":"RBBP7 (as a NuRD complex subunit) physically interacts with p300; overexpression of Rbbp7 reduces p300 protein levels, decreases tau acetylation at K280, and reduces tau phosphorylation at AT8 and AT100 epitopes; hippocampal Rbbp7 overexpression rescues neuronal death in the CA1 of PS19 tauopathy mice.","method":"In vitro overexpression in immortalized hippocampal cells and primary cortical neurons, in vivo hippocampal viral overexpression, Western blot for tau acetylation/phosphorylation, co-immunoprecipitation (Rbbp7-p300 interaction)","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro rescue experiments with molecular mechanism (p300-tau acetylation axis); single lab","pmids":["33978814"],"is_preprint":false},{"year":2021,"finding":"Double knockdown of Rbbp4 and Rbbp7 (but not individually) causes embryonic lethality during the morula-to-blastocyst transition in mice; RBBP4/7 depletion leads to cell cycle block, disrupted lineage specification, and a dramatic increase in H3.3 and H3K27ac abundance with H3.3 enrichment at promoters of RBBP4/7 target genes, revealing a compensatory role for RBBP4/7 in regulating histone H3.3 deposition during preimplantation development.","method":"siRNA knockdown in mouse embryos, RNA-seq, ChIP-seq, Western blot, immunofluorescence","journal":"Epigenetics","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with multiple orthogonal genomic and imaging readouts","pmids":["34709113"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, RbAp46/48 (LIN-53) and HAT-1 are required for histone H3 and H4 acetylation (H3K9ac, H4K5ac, H4K12ac), chromatinization of artificial chromosomes, and de novo CENP-A(HCP-3) and Mis18BP1(KNL-2) deposition at nascent centromeres; this requirement is distinct from centromere maintenance on endogenous chromosomes where Mis18BP1(KNL-2) acts upstream of RbAp46/48.","method":"RNAi depletion, immunofluorescence of centromeric and histone marks, artificial chromosome microinjection assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal readouts, epistasis with known centromere assembly factors","pmids":["33872374"],"is_preprint":false},{"year":2023,"finding":"A hemizygous loss-of-function variant in X-linked RBBP7 causes maturation arrest azoospermia; the mutation disrupts the sixth WD40 domain, abrogating interaction of RBBP7 with histone H4; in mouse spermatogonial and pachytene spermatocyte cells, Rbbp7 depletion causes cell cycle arrest and apoptosis with decreased BRCA1 and increased γH2AX; in Drosophila, germ-cell-specific knockdown of Caf1-55 eliminates germ cells (male infertility rescued by wild-type human RBBP7 but not mutant), while cyst-cell knockdown causes testicular hyperproliferation.","method":"Human genetic variant identification, co-immunoprecipitation (RBBP7-H4 interaction), siRNA knockdown in cell lines, flow cytometry, Western blot, Drosophila genetics with transgenic rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutagenesis + binding assay + in vitro and in vivo loss-of-function + cross-species rescue","pmids":["37843278"],"is_preprint":false},{"year":2025,"finding":"RBBP7 promotes breast cancer stemness and metastasis by recruiting the NuRD complex subunit LSD1; RBBP7 interacts with LSD1 and relies on LSD1 to erase H3K9me3 repressive marks at promoters of stemness genes (SOX9, SOX2, OCT4, CCND1), thereby transcriptionally upregulating them; CRISPR/Cas9 deletion of the RBBP7 super-enhancer decreases RBBP7 expression and suppresses malignant features.","method":"ChIP-qPCR, dual-luciferase reporter assay, Co-IP (RBBP7-LSD1 interaction), CRISPR/Cas9 SE deletion, tail vein injection metastasis model, PDO/PDX models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, Co-IP, CRISPR, and in vivo assays; single lab","pmids":["40038738"],"is_preprint":false},{"year":2025,"finding":"RBBP7 functions as an E3 ubiquitin ligase through covalent engagement of its Cys97 residue by ynamide electrophile-containing degrader compounds, enabling targeted protein degradation; chemical proteomics identified RBBP7 Cys97 as the covalent engagement site responsible for the degradation mechanism.","method":"Chemical proteomics (proteome profiling after ynamide compound treatment), functional validation of degradation, site-specific mutagenesis (Cys97)","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 2 — chemical proteomics with site-specific residue identification and functional validation; single study","pmids":["40600340"],"is_preprint":false},{"year":2025,"finding":"Rbbp7 mediates deacetylation of Acsl4 at lysine 401 (Acsl4-K401); this deacetylation increases Acsl4 enzyme activity by promoting ATP binding, thereby enhancing ferroptosis and promoting ovarian aging; Rbbp7 was identified as a direct mediator of Acsl4 deacetylation by immunoprecipitation-mass spectrometry.","method":"Acetyl-proteomic analysis, IP-MS identification of Rbbp7 as Acsl4 deacetylase, Western blot, in vivo/in vitro ferroptosis assays, pharmacological inhibition","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS identification + site-specific acetylation change + functional enzyme activity readout; single lab","pmids":["41478474"],"is_preprint":false},{"year":2025,"finding":"BAP1 forms a complex with YY1 and RBBP7 in clear cell renal cell carcinoma cells, and BAP1 knockdown alters gene expression profiles in ccRCC cells.","method":"Co-immunoprecipitation, gene expression profiling after BAP1 knockdown","journal":"Open life sciences","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP, limited mechanistic follow-up","pmids":["40688406"],"is_preprint":false}],"current_model":"RBBP7 (RbAp46) is a WD40-repeat histone chaperone that functions as a core scaffold subunit of multiple chromatin-regulatory complexes—including NuRD, Sin3-HDAC, PRC2, and CAF-1—where it binds histones H4 and H3 to recruit histone deacetylases, methyltransferases, and acetyltransferases to chromatin; it additionally acts as a substrate-receptor adaptor (DCAF) within CRL4 E3 ubiquitin ligase complexes to mediate ubiquitin-dependent loading of CENP-A at centromeres and proteasomal degradation of targets such as HUWE1; it is phosphorylated by AMPK to modulate its inhibitory interaction with DNMT1, thereby linking energy sensing to epigenetic regulation of gene expression; and its histone-binding and complex-scaffolding activities are essential for chromosome segregation, spermatogenesis, oocyte maturation, and stem cell maintenance."},"narrative":{"teleology":[{"year":1997,"claim":"The identification of RBBP7 as the histone-binding subunit that tethers the mSin3–HDAC1/2 co-repressor complex to chromatin established its foundational role as a histone chaperone bridging enzymes to their nucleosomal substrates.","evidence":"Biochemical purification and co-immunoprecipitation of the mSin3 complex from mammalian cells with functional transcription repression assays","pmids":["9150135"],"confidence":"High","gaps":["Structural basis of the RBBP7–histone H4 interaction was not resolved","Whether RBBP7 contributes catalytic selectivity versus mere tethering was unclear"]},{"year":1998,"claim":"Demonstrating that RBBP7 is a core subunit shared between the NuRD and Sin3-HDAC complexes—and not exclusive to one—reframed it as a general-purpose HDAC-delivery module used by multiple remodeling machines.","evidence":"Biochemical purification and mass spectrometry of the NuRD complex from multiple labs, showing RBBP7/RBBP4 as shared HDAC core components","pmids":["10444591","9885572","9804427"],"confidence":"High","gaps":["How specificity among NuRD versus Sin3 is achieved despite shared RBBP7 remained unknown","Stoichiometry within each complex was unresolved"]},{"year":2002,"claim":"The discovery that RBBP7 is an integral subunit of PRC2 with histone H3K27/K9 methyltransferase activity extended its functional repertoire beyond deacetylation to histone methylation-mediated Polycomb silencing.","evidence":"Biochemical reconstitution of PRC2 and in vitro HMT assay with SET-domain mutagenesis","pmids":["12435631"],"confidence":"High","gaps":["Whether RBBP7 contributes allosterically to PRC2 catalysis or acts solely as a histone-presenting platform was not distinguished"]},{"year":2004,"claim":"RNAi depletion of the Drosophila ortholog p55 revealed that RBBP7 is selectively required for RBF/E2F2-mediated repression of differentiation genes but dispensable for E2F1-driven proliferation targets, establishing functional specificity in gene repression.","evidence":"RNAi knockdown in Drosophila cells with RT-PCR of specific E2F target gene classes","pmids":["15456884"],"confidence":"High","gaps":["Mechanism distinguishing RBBP7-dependent from RBBP7-independent E2F repression was not identified"]},{"year":2013,"claim":"Linking RBBP7 to chromosome segregation fidelity, its depletion during oocyte maturation impaired histone deacetylation, chromosomal passenger complex localization, and spindle checkpoint function, causing aneuploidy.","evidence":"siRNA/morpholino knockdown in mouse oocytes with immunofluorescence of CPC components and chromosome segregation analysis","pmids":["24317350"],"confidence":"High","gaps":["Which HDAC-containing complex mediates the maturation-specific deacetylation was not determined","Whether RBBP7 acts independently of RBBP4 in this context was unclear"]},{"year":2015,"claim":"RBBP7 was shown to function as a DCAF substrate receptor in CRL4 E3 ubiquitin ligase complexes required for ubiquitin-dependent CENP-A loading at centromeres during G1, revealing an unexpected non-chromatin-remodeling role in centromere maintenance.","evidence":"RNAi depletion with quantitative CENP-A imaging and biochemical co-immunoprecipitation of CRL4 components in human cells","pmids":["25795299"],"confidence":"High","gaps":["The direct ubiquitination substrate at centromeres was not identified","Whether the CRL4-RBBP7 complex has substrates beyond CENP-A loading remained open"]},{"year":2016,"claim":"Cross-species conservation of RBBP7's centromere function was established when C. elegans LIN-53 depletion phenocopied CENP-A mislocalization and chromosome missegregation at holocentromeres, independent of known chromatin-modifying activities.","evidence":"RNAi in C. elegans with immunofluorescence and epistasis analysis with KNL-2 and CENP-A","pmids":["26904949"],"confidence":"High","gaps":["The molecular mechanism by which RBBP7 promotes CENP-A deposition independently of its HDAC/PRC2 roles was not resolved"]},{"year":2017,"claim":"AMPK was identified as a direct kinase for RBBP7, and phosphorylation enhanced RBBP7's inhibitory interaction with DNMT1, establishing a signaling axis from metabolic sensing through epigenetic modification to mitochondrial gene expression.","evidence":"Biochemical phosphorylation assay, co-immunoprecipitation, pharmacological AMPK activation in HUVECs, and AMPK-knockout mouse aorta studies","pmids":["28143904"],"confidence":"High","gaps":["The specific phosphorylation sites were not mapped at single-residue resolution","Whether AMPK-phosphorylated RBBP7 is selectively excluded from NuRD/PRC2 was not tested"]},{"year":2018,"claim":"RBBP7's DCAF function was extended to proteasomal degradation of HUWE1 via CRL4B, with downstream consequences for MCL-1 and BRCA1 stability, linking RBBP7 to apoptotic and DNA damage response regulation through ubiquitin-dependent proteolysis.","evidence":"Co-immunoprecipitation, ubiquitination assays, reciprocal overexpression/depletion of RBBP7 with monitoring of HUWE1, MCL-1, and BRCA1 protein levels","pmids":["29738775"],"confidence":"Medium","gaps":["Single-lab finding not yet independently confirmed","Whether RBBP7's CRL4 adaptor role extends to additional substrates was not explored systematically"]},{"year":2021,"claim":"Redundancy between RBBP7 and RBBP4 was resolved by showing that double, but not single, knockdown causes embryonic lethality at the morula-to-blastocyst transition with aberrant H3.3 deposition and hyperacetylation, revealing compensatory roles in restricting variant histone incorporation during preimplantation development.","evidence":"siRNA knockdown in mouse embryos with RNA-seq, ChIP-seq for H3.3 and H3K27ac, and immunofluorescence","pmids":["34709113"],"confidence":"High","gaps":["Whether H3.3 accumulation is a direct consequence of RBBP4/7 loss or secondary to HDAC/PRC2 dysfunction was not distinguished","Individual contributions of RBBP7 versus RBBP4 at specific loci remain unresolved"]},{"year":2023,"claim":"A hemizygous loss-of-function RBBP7 variant causing maturation arrest azoospermia in humans provided definitive genetic evidence that histone H4 binding by the sixth WD40 domain is essential for germ cell survival, confirmed by cross-species rescue in Drosophila.","evidence":"Human genetic variant identification, disrupted RBBP7–H4 co-immunoprecipitation, siRNA in spermatogonial cells, Drosophila germ-cell-specific knockdown with transgenic rescue by wild-type but not mutant human RBBP7","pmids":["37843278"],"confidence":"High","gaps":["Which chromatin complex is critically disrupted in germ cells was not determined","Whether female fertility is similarly affected by RBBP7 hemizygosity is unknown"]},{"year":2025,"claim":"RBBP7 was found to recruit LSD1 to stemness gene promoters in breast cancer, erasing H3K9me3 to activate SOX2/SOX9/OCT4 transcription, and separately to mediate deacetylation of the non-histone substrate Acsl4, enhancing ferroptosis in ovarian aging—expanding its functional scope to demethylation recruitment and non-histone substrate regulation.","evidence":"ChIP-qPCR, CRISPR super-enhancer deletion, PDX/PDO models for stemness; IP-MS, acetyl-proteomics, and ferroptosis assays for Acsl4 deacetylation","pmids":["40038738","41478474"],"confidence":"Medium","gaps":["Whether RBBP7 recruits LSD1 independently of NuRD is not resolved","The deacetylase that RBBP7 recruits to Acsl4 was not identified","Both findings from single labs await independent confirmation"]},{"year":null,"claim":"Key unresolved questions include which specific complex contexts mediate RBBP7's distinct functions (centromere assembly, germ cell survival, ferroptosis), how post-translational modifications partition RBBP7 among competing complexes, and whether a high-resolution structure of full-length RBBP7 within NuRD or CRL4 can explain its multivalent substrate recognition.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution cryo-EM structure of RBBP7 within intact NuRD or CRL4 complex","Post-translational modification map (beyond AMPK phosphorylation) not systematically determined","Relative contribution of RBBP7 versus RBBP4 in individual complex contexts remains unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,6,11,15,21,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,14,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,6,10,11,14]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[11,12,15,21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,6,11,20,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,14,23]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,12,15,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,18,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,7,22]}],"complexes":["NuRD","Sin3-HDAC","PRC2","CRL4"],"partners":["HDAC1","HDAC2","MTA2","DDB1","CUL4B","DNMT1","LSD1","CENP-A"],"other_free_text":[]},"mechanistic_narrative":"RBBP7 (RbAp46) is a WD40-repeat histone-binding protein that serves as a shared scaffold subunit within multiple chromatin-regulatory complexes—including NuRD, Sin3-HDAC, PRC2, and CAF-1—where it bridges histone substrates (primarily H4) to enzymes that deacetylate, methylate, or remodel chromatin, thereby mediating transcriptional repression and epigenetic gene regulation [PMID:9150135, PMID:10444591, PMID:12435631]. RBBP7 additionally functions as a DDB1-CUL4-associated factor (DCAF) substrate receptor in CRL4 E3 ubiquitin ligase complexes, directing ubiquitin-dependent CENP-A loading at centromeres and proteasomal degradation of targets such as HUWE1 [PMID:25795299, PMID:29738775]. AMPK-mediated phosphorylation of RBBP7 enhances its inhibitory interaction with DNMT1, coupling metabolic sensing to DNA methylation and mitochondrial biogenesis gene expression [PMID:28143904]. A hemizygous loss-of-function variant in X-linked RBBP7 that disrupts histone H4 binding causes maturation arrest azoospermia in humans, with cross-species rescue confirming a cell-autonomous requirement in germ cell survival [PMID:37843278]."},"prefetch_data":{"uniprot":{"accession":"Q16576","full_name":"Histone-binding protein RBBP7","aliases":["Histone acetyltransferase type B subunit 2","Nucleosome-remodeling factor subunit RBAP46","Retinoblastoma-binding protein 7","RBBP-7","Retinoblastoma-binding protein p46"],"length_aa":425,"mass_kda":47.8,"function":"Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBBP7","classification":"Not 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inhibits cell growth and colony formation, identifying it as a downstream effector of WT1-mediated growth suppression.\",\n      \"method\": \"Suppression subtractive hybridization PCR, colony formation assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct identification of WT1→RBBP7 transcriptional axis with functional readout, single lab\",\n      \"pmids\": [\"9765217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RbAp46 (RBBP7) interacts with the BRCT domain of BRCA1 via its first two WD-repeat domains (demonstrated by yeast two-hybrid and co-immunoprecipitation), and this interaction represses BRCA1-mediated transactivation of the p21 promoter; the interaction is disrupted in response to DNA-damaging agents.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay, DNA damage treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal binding and functional reporter assay in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11394910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of RbAp46 (RBBP7) activates the c-Jun N-terminal kinase (JNK) signaling pathway, triggering apoptosis; a dominant-negative JNK1 mutant blocks RbAp46-induced apoptosis, placing RBBP7 upstream of JNK in an apoptotic cascade.\",\n      \"method\": \"Tetracycline-inducible expression system, dominant-negative JNK1 mutant epistasis, cell viability assays, xenograft tumor assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with dominant-negative and in vivo validation, single lab\",\n      \"pmids\": [\"14981905\", \"12767060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Drosophila ortholog of RbAp46/RbAp48, p55 (dCAF-1), is essential for repression of dE2F2/RBF-regulated target genes; RNAi depletion of p55 deregulates E2F targets normally repressed by dE2F2/RBF1 and dE2F2/RBF2 in a cell-cycle-independent manner, demonstrating a conserved function in pRB-related repression.\",\n      \"method\": \"RNA interference (RNAi) depletion in Drosophila cells, gene expression analysis of E2F target genes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean RNAi KD with defined transcriptional phenotype and epistatic ordering in Drosophila ortholog system, replicated across target sets\",\n      \"pmids\": [\"15456884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RbAp46 (RBBP7) expression increases GSK-3β levels, leading to hyperphosphorylation and degradation of β-catenin and reduced β-catenin/TCF nuclear signaling, indicating RBBP7 suppresses the Wnt pathway through upregulation of GSK-3β.\",\n      \"method\": \"Stable overexpression in mammary epithelial cells, Western blot, luciferase reporter assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single approach, no direct mechanistic link established between RBBP7 and GSK-3β\",\n      \"pmids\": [\"17201172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBBP7 is a component of histone deacetylase-containing complexes that mediates histone deacetylation during mouse oocyte maturation; its depletion (siRNA/morpholino) prevents the maturation-associated decrease in histone acetylation, causing mislocalization and dysfunction of the chromosomal passenger complex (CPC), resulting in chromosome misalignment, improper kinetochore-microtubule attachments, impaired spindle assembly checkpoint, cytokinesis defects, and aneuploidy.\",\n      \"method\": \"siRNA/morpholino knockdown in mouse oocytes, immunofluorescence, chromosome segregation assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined phenotypic readouts and mechanistic link to CPC localization via histone deacetylation\",\n      \"pmids\": [\"24317350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBBP7 functions as a substrate-specific adaptor (DCAF) within the CUL4-DDB1-RING E3 ubiquitin ligase complex (CRL4); this CRL4(RBBP7) complex is required for centromeric loading of newly synthesized CENP-A during G1 phase, in addition to RBBP7's role in binding and stabilizing soluble pre-nucleosomal CENP-A.\",\n      \"method\": \"Biochemical fractionation, quantitative imaging, siRNA knockdown of CUL4/DDB1/RBBP7, CENP-A localization assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combined biochemical and quantitative imaging with clean KD, multiple complex components tested, mechanistic conclusion supported by multiple orthogonal methods\",\n      \"pmids\": [\"25795299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In C. elegans, RbAp46/48 (LIN-53) is required for CENP-A (HCP-3) localization at holocentromeres; LIN-53 and CENP-A localizations are interdependent, and LIN-53 is recruited to centromeres during metaphase in a CENP-A- and M18BP1(KNL-2)-dependent manner. This centromeric function is independent of known chromatin-modifying complexes containing LIN-53.\",\n      \"method\": \"RNAi depletion in C. elegans, immunofluorescence, epistasis analysis of centromere assembly hierarchy\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean RNAi with defined centromere assembly phenotype and epistatic ordering using multiple complex components\",\n      \"pmids\": [\"26904949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RbAp46 (RBBP7) binds to HDAC1 and transcription factor Sp1, and this complex is recruited to the RECK promoter at the Sp1-binding site, repressing RECK transcription; this mechanism promotes MMP-9 activity and metastasis downstream of oncogenic Ha-Ras.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), DNA affinity precipitation assay (DAPA), RECK reporter assay, lentiviral shRNA knockdown, xenograft metastasis model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and DAPA confirm complex at RECK promoter, functional shRNA validation in vivo, single lab\",\n      \"pmids\": [\"25885317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBBP7 silencing in mouse uterine stromal cells compromises decidualization by attenuating histone H4 acetylation and reducing cyclin D3 expression, and its expression is induced by progesterone/nuclear receptor PR signaling.\",\n      \"method\": \"siRNA knockdown in primary uterine stromal cells, in vitro decidualization model, in situ hybridization, immunochemistry\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA KD with defined epigenetic and cell differentiation phenotype, single lab\",\n      \"pmids\": [\"26040671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK directly phosphorylates RBBP7 at a consensus AMPK site; phosphorylated RBBP7 shows increased interaction with DNMT1, inhibiting DNMT1-mediated DNA methylation, thereby promoting a more open chromatin structure and increased expression of mitochondrial biogenesis genes (e.g., PGC-1α).\",\n      \"method\": \"In vitro AMPK phosphorylation assay, co-immunoprecipitation, pharmacological AMPK activation, pulsatile shear stress in HUVECs, mouse aorta studies with AMPK activators\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct phosphorylation assay plus co-IP, replicated in cells and in vivo, multiple orthogonal approaches\",\n      \"pmids\": [\"28143904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The human MTA2-RBBP7 sub-complex of the NuRD complex can be isolated as a stable unit; negative stain electron microscopy reveals an elongated architecture with hinge-like motion, consistent with a 2:4 stoichiometry (MTA:RBBP) observed for the Drosophila ortholog, and RBBP7 plays a central role in initial NuRD complex assembly.\",\n      \"method\": \"Protein expression/purification from HEK293F cells, negative stain electron microscopy, 3D volume reconstruction\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structural EM with purified complex, but limited functional validation\",\n      \"pmids\": [\"28179136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBBP7 is the DDB1-Cullin Associated Factor (DCAF) within the CRL4B (CUL4B-ROC1-DDB1) E3 ubiquitin ligase complex that bridges the complex to its substrate HUWE1, promoting polyubiquitination and proteasomal degradation of HUWE1; RBBP7 depletion stabilizes HUWE1 and accelerates degradation of HUWE1 substrates MCL-1 and BRCA1.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown experiments, Western blot for ubiquitination and protein stability\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and gain/loss-of-function with substrate tracking, single lab\",\n      \"pmids\": [\"29738775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBBP7 and its partner HAT-1 are required in C. elegans for initial de novo CENP-A(HCP-3) and Mis18BP1(KNL-2) deposition at nascent artificial chromosomes (de novo centromere formation), linked to their role in promoting H3 and H4 acetylation during chromatinization; this function differs from centromere maintenance on endogenous chromosomes.\",\n      \"method\": \"RNAi depletion in C. elegans, microinjection of artificial chromosomes, immunofluorescence, histone acetylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean RNAi with defined de novo centromere assembly phenotype and epistatic ordering relative to KNL-2\",\n      \"pmids\": [\"33872374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBBP7 depletion in mouse preimplantation embryos (double knockdown with RBBP4) causes embryonic lethality at morula-to-blastocyst transition, accompanied by cell cycle block, disrupted lineage specification, and a dramatic increase in histone H3.3 and H3K27ac abundance; ChIP-seq showed H3.3 enrichment at promoters of RBBP4/7 target genes.\",\n      \"method\": \"Double siRNA knockdown in mouse embryos, RNA-seq, ChIP-seq, immunofluorescence, embryo development assays\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple omics approaches with defined phenotype, but RBBP7 individual role not cleanly separated from RBBP4\",\n      \"pmids\": [\"34709113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBBP7 overexpression in immortalized hippocampal cells and primary cortical neurons reduces p300 levels, lowers tau acetylation at lysine 280, and decreases tau phosphorylation at AT8 and AT100 sites, rescuing TauP301L-induced cytotoxicity; hippocampal RBBP7 overexpression in PS19 mice rescued CA1 neuronal death.\",\n      \"method\": \"In vitro overexpression in cell lines and primary neurons, in vivo AAV-mediated hippocampal overexpression in PS19 mice, Western blot for tau modifications, immunohistochemistry\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation with defined molecular mechanism (p300→tau acetylation→tau phosphorylation), multiple model systems\",\n      \"pmids\": [\"33978814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A hemizygous loss-of-function mutation in RBBP7 (affecting the sixth WD40 domain) disrupts interaction with histone H4, and causes maturation arrest in spermatogenesis; RBBP7 loss in mouse spermatogonial/spermatocyte cells leads to cell cycle arrest and apoptosis. Knockdown of the Drosophila ortholog (Caf1-55) in germ cells abolishes germ cells, while knockdown in cyst cells causes hyperproliferation; wild-type human RBBP7 (but not the WD40 mutant) rescues infertility.\",\n      \"method\": \"Human genetics (hemizygous variant identification), in vitro interaction assay (RBBP7-histone H4), siRNA in mouse spermatocyte cells, Drosophila genetic knockdown, rescue experiments with wild-type vs. mutant RBBP7\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutation-disrupted H4 interaction, genetic epistasis in Drosophila, cross-species rescue demonstrating WD40 domain requirement, multiple model systems\",\n      \"pmids\": [\"37843278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBBP7 forms a trimeric complex with the lncRNA FIT and p53; this complex facilitates p53 acetylation and p53-mediated transcription of the FAS gene in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (RNA-protein complex), luciferase reporter assay, loss-of-function experiments\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying complex, limited mechanistic follow-up for RBBP7's specific role\",\n      \"pmids\": [\"37225855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 is identified as a component of a BAP1 complex with YY1 in clear cell renal cell carcinoma (ccRCC) cells, implicating RBBP7 in BAP1-dependent transcriptional regulation.\",\n      \"method\": \"Co-immunoprecipitation, gene expression profiling after BAP1 knockdown\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying complex, minimal mechanistic follow-up for RBBP7\",\n      \"pmids\": [\"40688406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 acts as a direct mediator of Acsl4 deacetylation at K401 in ovarian granulosa cells; RBBP7 was identified as an Acsl4-interacting protein by immunoprecipitation-mass spectrometry, and deacetylation at Acsl4-K401 increases Acsl4 enzyme activity by promoting ATP binding, thereby enhancing ferroptosis and ovarian aging.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (IP-MS), acetyl-proteomics, Western blot, in vitro enzyme activity assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS identification with site-specific acetylation and functional enzyme activity readout, novel substrate for RBBP7 deacetylase function\",\n      \"pmids\": [\"41478474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 interacts with LSD1 and recruits it to promoters of stemness genes (SOX9, SOX2, OCT4, CCND1), where LSD1 erases repressive H3K9me3 marks, transcriptionally upregulating these genes and promoting cancer stem cell properties and metastasis in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-qPCR, CRISPR/Cas9-mediated super-enhancer deletion, gene expression analysis, tumor sphere formation, tail vein metastasis assay\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP-qPCR at target promoters, multiple functional assays in single lab\",\n      \"pmids\": [\"40038738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cys97 of RBBP7 functions as an E3 ubiquitin ligase active site that can be covalently engaged by ynamide electrophiles; RBBP7 E3 ligase activity was identified by chemical proteomics and validated as responsible for degradation of target proteins in targeted protein degradation (TPD) applications.\",\n      \"method\": \"Chemical proteomics (activity-based protein profiling), covalent probe engagement, proteome profiling, functional degrader assays\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — chemical proteomics with covalent site identification and functional degradation validation\",\n      \"pmids\": [\"40600340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBBP7 is a WD40-repeat histone chaperone and chromatin adaptor that serves as an integral subunit of multiple epigenetic complexes (NuRD, SIN3A, CAF-1, CoREST, CRL4) where it bridges these complexes to histone substrates (particularly H4) and to specific targets for ubiquitination (e.g., HUWE1 via CRL4B); it is directly phosphorylated by AMPK to enhance interaction with and inhibition of DNMT1, promotes CENP-A loading at centromeres as a CRL4 adaptor, mediates histone deacetylation required for chromosomal passenger complex function in meiosis, suppresses tau acetylation by reducing p300 levels, and deacetylates non-histone substrates such as Acsl4, while its WD40 domain integrity is required for histone H4 binding and spermatogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"RbAp46 (RBBP7) and RbAp48 are components of the NuRD multisubunit complex, which contains both ATP-dependent nucleosome remodeling and histone deacetylase (HDAC1/2) activities; RbAp46/48 form a core histone deacetylase complex shared between NuRD and Sin3-HDAC complexes, and MTA2 modulates the enzymatic activity of this core complex.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, mass spectrometry identification of complex subunits\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution of complex, replicated across multiple labs (Zhang 1998, Xue 1998, Tong 1998, Wade 1999)\",\n      \"pmids\": [\"10444591\", \"9885572\", \"9804427\", \"9790534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RbAp46/RbAp48 (RBBP7/RBBP4) are histone-binding proteins that tether the mSin3 co-repressor complex (containing HDAC1 and HDAC2) to core histone proteins, enabling transcriptional repression.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, functional transcription repression assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical complex reconstitution, replicated\",\n      \"pmids\": [\"9150135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RbAp46/48 are subunits of the Mi-2/NuRD complex in Xenopus and human cells, which couples DNA methylation to histone deacetylation and chromatin remodeling; MBD2 directs the complex to methylated DNA.\",\n      \"method\": \"Biochemical purification from Xenopus egg extracts and human cell lines, subunit identification by mass spectrometry and cloning\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution across species, replicated by multiple labs\",\n      \"pmids\": [\"10471499\", \"10471500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RbAp46 (RBBP7) is transcriptionally induced ~15-fold by the Wilms' tumor suppressor WT1, and its overexpression inhibits cell growth and colony formation, identifying it as a mediator of WT1-dependent growth inhibition.\",\n      \"method\": \"Suppression subtractive hybridization PCR to identify WT1 target genes; colony formation and growth rate assays in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene expression induction confirmed, functional readout (colony formation, growth rate) with mechanistic link to WT1\",\n      \"pmids\": [\"9765217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RbAp46 (RBBP7) interacts specifically with the BRCT domain of BRCA1 via its first two WD-repeat domains, and represses BRCA1-mediated transactivation of the p21 promoter; this interaction is disrupted by DNA-damaging agents.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, luciferase transactivation assay, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed, functional transactivation assay, DNA damage disruption shown\",\n      \"pmids\": [\"11394910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RbAp46 (RBBP7) overexpression suppresses clonal growth of HEK293 cells in soft agar, inhibits tumor growth in nude mice, increases the G2/M cell fraction, and augments apoptosis in serum-starved cells.\",\n      \"method\": \"Soft agar colony formation, nude mouse xenograft, cell cycle analysis (flow cytometry), apoptosis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional readouts in same study\",\n      \"pmids\": [\"11433396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RbAp46/RbAp48 (RBBP7/RBBP4) are components of the PRC2 (Polycomb repressive complex 2), which contains Enhancer of Zeste, Extra sex combs, and Su(z)12, and possesses histone methyltransferase activity specific for H3K9 and H3K27; the HMT activity requires an intact SET domain in E(z).\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, histone methyltransferase assay, domain mutagenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro HMT assay with mutagenesis, replicated\",\n      \"pmids\": [\"12435631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RbAp46 (RBBP7) inducible expression activates the c-Jun NH2-terminal kinase (JNK) pathway and triggers apoptosis; a dominant-negative JNK1 mutant blocks RbAp46-mediated apoptosis, placing RbAp46 upstream of JNK in a pro-apoptotic pathway.\",\n      \"method\": \"Tetracycline-inducible expression system, JNK kinase assay, dominant-negative JNK1 epistasis, xenograft tumor model\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with dominant-negative mutant establishes pathway position\",\n      \"pmids\": [\"14981905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Drosophila ortholog of RbAp46/48, p55/dCAF-1, is essential for repression of dE2F2-regulated target genes by RBF1 and RBF2 complexes; RNAi depletion of p55 specifically deregulates cell cycle-independent E2F2 targets without affecting proliferation-coupled E2F1 targets, revealing mechanistically distinct repression pathways.\",\n      \"method\": \"RNAi depletion in Drosophila cells, RT-PCR of E2F target genes, genetic epistasis analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi loss-of-function with specific target gene readouts, epistasis distinguishing two repression pathways\",\n      \"pmids\": [\"15456884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RbAp46 (RBBP7) expression in mammary epithelial cells increases GSK-3β expression, leading to hyperphosphorylation and reduced steady-state levels of β-catenin, thereby suppressing β-catenin/TCF nuclear signaling and cell growth.\",\n      \"method\": \"Stable transfection, Western blot, luciferase reporter assay for β-catenin/TCF signaling\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Western blot + reporter assay, pathway placement indirect\",\n      \"pmids\": [\"17201172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUMO-1 forms a protein complex with RbAp46 (RBBP7) in the nucleus (co-localization and co-immunoprecipitation), stabilizing RbAp46 protein levels post-translationally without sumoylating RbAp46 directly; SUMO-1-mediated stabilization of RbAp46 enhances suppression of Ras-induced cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, Western blot, cell growth assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single Co-IP method; mechanism of stabilization not fully resolved\",\n      \"pmids\": [\"19189660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBBP7 is a dormant maternal mRNA recruited for translation during mouse oocyte maturation to regulate histone deacetylation; RBBP7 depletion by siRNA/morpholino impairs maturation-associated histone deacetylation, which in turn is required for chromosomal passenger complex (CPC) localization and function, causing chromosome misalignment, improper kinetochore-microtubule attachments, impaired spindle assembly checkpoint, cytokinesis defects, and increased aneuploidy at metaphase II.\",\n      \"method\": \"siRNA/morpholino knockdown, immunofluorescence of CPC components, histone acetylation assays, chromosome segregation analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts linking RBBP7 to histone deacetylation and CPC function\",\n      \"pmids\": [\"24317350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBBP7 acts as a substrate-specific adaptor (DCAF) in the CRL4 (CUL4-DDB1-ROC1) E3 ubiquitin ligase complex; CRL4(RBBP7) is required for ubiquitin-dependent loading of newly synthesized CENP-A at centromeres during G1, and RBBP7 also stabilizes soluble pre-nucleosomal CENP-A.\",\n      \"method\": \"RNAi depletion, quantitative imaging of CENP-A dynamics, biochemical co-immunoprecipitation, cell cycle staging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical and imaging methods combined, specific CRL4 adaptor function demonstrated\",\n      \"pmids\": [\"25795299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rbbp7 expression in mouse uterine stromal cells is induced by progesterone-nuclear receptor PR signaling; siRNA knockdown of Rbbp7 in primary murine stromal cells compromises decidualization by attenuating histone H4 acetylation and cyclin D3 expression.\",\n      \"method\": \"In situ hybridization, immunochemistry, siRNA knockdown, in vitro decidualization model, histone acetylation assay, Western blot\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific epigenetic and cell-differentiation readouts\",\n      \"pmids\": [\"26040671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RbAp46 (RBBP7) is upregulated by oncogenic Ha-ras and forms a complex with HDAC1 and Sp1 that binds the RECK promoter at Sp1 sites, repressing RECK expression and thereby increasing MMP-9 activity and promoting lung metastasis in vivo.\",\n      \"method\": \"Suppression subtractive hybridization PCR, ChIP assay, DNA affinity precipitation, RECK reporter gene assay, shRNA knockdown, xenograft nude mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (ChIP, DAPA, reporter assay) with in vivo validation\",\n      \"pmids\": [\"25885317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RbAp46/48 (LIN-53), the C. elegans ortholog of RBBP7, is required for CENP-A(HCP-3) localization at holocentromeres; its centromeric localization during metaphase is interdependent with CENP-A and depends on M18BP1(KNL-2); depletion causes anaphase bridges and chromosome missegregation, and this function is independent of histone acetylation, H3K27 trimethylation, or known chromatin-modifying complexes.\",\n      \"method\": \"RNAi depletion in C. elegans, immunofluorescence of centromere/kinetochore proteins, epistasis analysis with KNL-2 and CENP-A\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis analysis with multiple centromere components, orthogonal imaging and genetic methods\",\n      \"pmids\": [\"26904949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK directly phosphorylates RBBP7 at consensus phosphorylation sequences; AMPK-mediated phosphorylation of RBBP7 increases its interaction with and inhibition of DNMT1, contributing to reduced DNA methylation and increased expression of mitochondrial biogenesis genes (PGC-1α, Tfam, UCP2, UCP3).\",\n      \"method\": \"Consensus sequence analysis, biochemical phosphorylation assays, co-immunoprecipitation, pharmacological AMPK activation, pulsatile shear stress in HUVECs, mouse aorta studies with AMPKα2 knockout\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct phosphorylation demonstrated biochemically, functional consequence confirmed in cells and in vivo with genetic controls\",\n      \"pmids\": [\"28143904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The human MTA2-RBBP7 sub-complex of NuRD can be isolated as a stable entity; negative stain electron microscopy reveals an elongated architecture capable of hinge-like motion, with stoichiometry analogous to the Drosophila NuRD MTA-RBBP complex (2:4 MTA:RBBP), suggesting MTA-RBBP is a stable core module for NuRD assembly.\",\n      \"method\": \"HEK293F cell expression, biochemical purification, negative stain electron microscopy, 3D reconstruction\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural EM with purified complex; single study without higher-resolution validation\",\n      \"pmids\": [\"28179136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBBP7 is the substrate-receptor (DCAF) in the CRL4B E3 ubiquitin ligase complex (CRL4B-RBBP7) that bridges DDB1-CUL4B-ROC1 to HUWE1, mediating HUWE1 polyubiquitination and proteasomal degradation; RBBP7 overexpression promotes HUWE1 degradation, while RBBP7 depletion stabilizes HUWE1 and accelerates degradation of MCL-1 and BRCA1.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/depletion experiments, ubiquitination assay, Western blot for substrate levels\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function experiments, ubiquitination assay; single lab\",\n      \"pmids\": [\"29738775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBBP7 (as a NuRD complex subunit) physically interacts with p300; overexpression of Rbbp7 reduces p300 protein levels, decreases tau acetylation at K280, and reduces tau phosphorylation at AT8 and AT100 epitopes; hippocampal Rbbp7 overexpression rescues neuronal death in the CA1 of PS19 tauopathy mice.\",\n      \"method\": \"In vitro overexpression in immortalized hippocampal cells and primary cortical neurons, in vivo hippocampal viral overexpression, Western blot for tau acetylation/phosphorylation, co-immunoprecipitation (Rbbp7-p300 interaction)\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro rescue experiments with molecular mechanism (p300-tau acetylation axis); single lab\",\n      \"pmids\": [\"33978814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Double knockdown of Rbbp4 and Rbbp7 (but not individually) causes embryonic lethality during the morula-to-blastocyst transition in mice; RBBP4/7 depletion leads to cell cycle block, disrupted lineage specification, and a dramatic increase in H3.3 and H3K27ac abundance with H3.3 enrichment at promoters of RBBP4/7 target genes, revealing a compensatory role for RBBP4/7 in regulating histone H3.3 deposition during preimplantation development.\",\n      \"method\": \"siRNA knockdown in mouse embryos, RNA-seq, ChIP-seq, Western blot, immunofluorescence\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with multiple orthogonal genomic and imaging readouts\",\n      \"pmids\": [\"34709113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, RbAp46/48 (LIN-53) and HAT-1 are required for histone H3 and H4 acetylation (H3K9ac, H4K5ac, H4K12ac), chromatinization of artificial chromosomes, and de novo CENP-A(HCP-3) and Mis18BP1(KNL-2) deposition at nascent centromeres; this requirement is distinct from centromere maintenance on endogenous chromosomes where Mis18BP1(KNL-2) acts upstream of RbAp46/48.\",\n      \"method\": \"RNAi depletion, immunofluorescence of centromeric and histone marks, artificial chromosome microinjection assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal readouts, epistasis with known centromere assembly factors\",\n      \"pmids\": [\"33872374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A hemizygous loss-of-function variant in X-linked RBBP7 causes maturation arrest azoospermia; the mutation disrupts the sixth WD40 domain, abrogating interaction of RBBP7 with histone H4; in mouse spermatogonial and pachytene spermatocyte cells, Rbbp7 depletion causes cell cycle arrest and apoptosis with decreased BRCA1 and increased γH2AX; in Drosophila, germ-cell-specific knockdown of Caf1-55 eliminates germ cells (male infertility rescued by wild-type human RBBP7 but not mutant), while cyst-cell knockdown causes testicular hyperproliferation.\",\n      \"method\": \"Human genetic variant identification, co-immunoprecipitation (RBBP7-H4 interaction), siRNA knockdown in cell lines, flow cytometry, Western blot, Drosophila genetics with transgenic rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis + binding assay + in vitro and in vivo loss-of-function + cross-species rescue\",\n      \"pmids\": [\"37843278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 promotes breast cancer stemness and metastasis by recruiting the NuRD complex subunit LSD1; RBBP7 interacts with LSD1 and relies on LSD1 to erase H3K9me3 repressive marks at promoters of stemness genes (SOX9, SOX2, OCT4, CCND1), thereby transcriptionally upregulating them; CRISPR/Cas9 deletion of the RBBP7 super-enhancer decreases RBBP7 expression and suppresses malignant features.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter assay, Co-IP (RBBP7-LSD1 interaction), CRISPR/Cas9 SE deletion, tail vein injection metastasis model, PDO/PDX models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, Co-IP, CRISPR, and in vivo assays; single lab\",\n      \"pmids\": [\"40038738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 functions as an E3 ubiquitin ligase through covalent engagement of its Cys97 residue by ynamide electrophile-containing degrader compounds, enabling targeted protein degradation; chemical proteomics identified RBBP7 Cys97 as the covalent engagement site responsible for the degradation mechanism.\",\n      \"method\": \"Chemical proteomics (proteome profiling after ynamide compound treatment), functional validation of degradation, site-specific mutagenesis (Cys97)\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical proteomics with site-specific residue identification and functional validation; single study\",\n      \"pmids\": [\"40600340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbbp7 mediates deacetylation of Acsl4 at lysine 401 (Acsl4-K401); this deacetylation increases Acsl4 enzyme activity by promoting ATP binding, thereby enhancing ferroptosis and promoting ovarian aging; Rbbp7 was identified as a direct mediator of Acsl4 deacetylation by immunoprecipitation-mass spectrometry.\",\n      \"method\": \"Acetyl-proteomic analysis, IP-MS identification of Rbbp7 as Acsl4 deacetylase, Western blot, in vivo/in vitro ferroptosis assays, pharmacological inhibition\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS identification + site-specific acetylation change + functional enzyme activity readout; single lab\",\n      \"pmids\": [\"41478474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAP1 forms a complex with YY1 and RBBP7 in clear cell renal cell carcinoma cells, and BAP1 knockdown alters gene expression profiles in ccRCC cells.\",\n      \"method\": \"Co-immunoprecipitation, gene expression profiling after BAP1 knockdown\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, limited mechanistic follow-up\",\n      \"pmids\": [\"40688406\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBBP7 (RbAp46) is a WD40-repeat histone chaperone that functions as a core scaffold subunit of multiple chromatin-regulatory complexes—including NuRD, Sin3-HDAC, PRC2, and CAF-1—where it binds histones H4 and H3 to recruit histone deacetylases, methyltransferases, and acetyltransferases to chromatin; it additionally acts as a substrate-receptor adaptor (DCAF) within CRL4 E3 ubiquitin ligase complexes to mediate ubiquitin-dependent loading of CENP-A at centromeres and proteasomal degradation of targets such as HUWE1; it is phosphorylated by AMPK to modulate its inhibitory interaction with DNMT1, thereby linking energy sensing to epigenetic regulation of gene expression; and its histone-binding and complex-scaffolding activities are essential for chromosome segregation, spermatogenesis, oocyte maturation, and stem cell maintenance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RBBP7 is a WD40-repeat protein that functions as a histone chaperone and chromatin adaptor, serving as an integral subunit of multiple epigenetic complexes—including NuRD, CRL4, and CAF-1—where it bridges these complexes to histone substrates and specific ubiquitination targets. Through its role in histone deacetylase complexes, RBBP7 mediates histone deacetylation required for chromosomal passenger complex function during meiosis, centromeric CENP-A loading during G1 phase as a CRL4 DCAF adaptor, and de novo centromere formation, while also deacetylating the non-histone substrate Acsl4 to regulate ferroptosis [PMID:24317350, PMID:25795299, PMID:33872374, PMID:41478474]. AMPK-mediated phosphorylation of RBBP7 enhances its interaction with DNMT1 to inhibit DNA methylation and promote mitochondrial biogenesis gene expression, and RBBP7 suppresses pathological tau acetylation by reducing p300 levels, rescuing tauopathy-associated neurodegeneration in vivo [PMID:28143904, PMID:33978814]. A hemizygous loss-of-function mutation in the sixth WD40 domain of RBBP7 disrupts histone H4 binding and causes spermatogenic maturation arrest and male infertility [PMID:37843278].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that RBBP7 is a growth-suppressive target of WT1 that physically engages the Rb pathway answered whether RBBP7 has a functional role beyond being a histone-binding scaffold.\",\n      \"evidence\": \"Suppression subtractive hybridization, colony formation assays, and co-immunoprecipitation in tumor cell lines\",\n      \"pmids\": [\"9765217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking WT1-induced RBBP7 to growth suppression not resolved\", \"Rb interaction domain on RBBP7 not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of RBBP7-BRCA1 interaction via WD40 repeats, disrupted by DNA damage, revealed that RBBP7 modulates BRCA1 transcriptional activity in a damage-responsive manner.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and luciferase reporter assay for p21 promoter activity\",\n      \"pmids\": [\"11394910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of BRCA1-RBBP7 interaction during DNA damage response not established in vivo\", \"Whether interaction is direct or complex-mediated not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Drosophila ortholog studies established that RBBP7/p55 is essential for E2F/Rb-mediated gene repression in a cell-cycle-independent manner, demonstrating a conserved chromatin-based transcriptional repressor function.\",\n      \"evidence\": \"RNAi depletion of p55 in Drosophila cells with analysis of E2F target gene derepression\",\n      \"pmids\": [\"15456884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific RBBP7-containing complex mediates E2F/Rb repression not determined\", \"Mammalian validation of cell-cycle-independent role incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that RBBP7 depletion in oocytes blocks maturation-associated histone deacetylation and causes CPC mislocalization linked RBBP7's HDAC complex role to chromosome segregation fidelity in meiosis.\",\n      \"evidence\": \"siRNA/morpholino knockdown in mouse oocytes with immunofluorescence and chromosome segregation assays\",\n      \"pmids\": [\"24317350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific HDAC complex (NuRD, SIN3A, or other) mediates the meiotic function not identified\", \"Whether RBBP7 vs RBBP4 have distinct meiotic roles not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that RBBP7 acts as a DCAF within CRL4 to load CENP-A at centromeres, conserved in C. elegans where it is required independently of its chromatin-modifying complex roles, established a non-canonical centromere assembly function for RBBP7.\",\n      \"evidence\": \"Biochemical fractionation and quantitative imaging with siRNA knockdown of CUL4/DDB1/RBBP7 in human cells; RNAi epistasis analysis in C. elegans\",\n      \"pmids\": [\"25795299\", \"26904949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination substrate at centromeres not identified\", \"Whether CRL4-RBBP7 ubiquitylates a centromere component or acts non-catalytically not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of AMPK-mediated phosphorylation of RBBP7 that enhances DNMT1 binding and inhibits DNA methylation revealed a signaling-responsive regulatory switch controlling RBBP7's epigenetic output.\",\n      \"evidence\": \"In vitro AMPK phosphorylation assay, co-immunoprecipitation, pharmacological AMPK activation in HUVECs and mouse aorta\",\n      \"pmids\": [\"28143904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site identity and structural basis for enhanced DNMT1 binding not determined\", \"Whether other kinases regulate RBBP7 not explored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Structural analysis of the MTA2-RBBP7 sub-complex by negative-stain EM revealed RBBP7's central role in NuRD assembly with an elongated 2:4 MTA:RBBP architecture.\",\n      \"evidence\": \"Purified MTA2-RBBP7 complex from HEK293F cells, negative stain EM with 3D reconstruction\",\n      \"pmids\": [\"28179136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution structure not yet available for this sub-complex\", \"Functional consequence of hinge-like motion not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"RBBP7 was shown to serve as the DCAF that bridges CRL4B to its substrate HUWE1 for polyubiquitination and degradation, expanding RBBP7's adaptor role beyond centromere biology to regulation of protein homeostasis.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown with Western blot for HUWE1 ubiquitination and stability\",\n      \"pmids\": [\"29738775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between RBBP7 and HUWE1 not shown with purified proteins\", \"Whether RBBP7-CRL4B targets additional substrates beyond HUWE1 not explored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple discoveries in 2021 extended RBBP7's functions: it promotes de novo centromere formation with HAT-1 via H3/H4 acetylation in C. elegans, is essential (with RBBP4) for preimplantation embryo development by controlling histone H3.3 dynamics, and suppresses tau acetylation through p300 downregulation to rescue tauopathy in vivo.\",\n      \"evidence\": \"C. elegans artificial chromosome assay with RNAi; double siRNA knockdown in mouse embryos with RNA-seq/ChIP-seq; AAV-mediated hippocampal overexpression in PS19 tauopathy mice\",\n      \"pmids\": [\"33872374\", \"34709113\", \"33978814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RBBP7 reduces p300 levels not defined\", \"Individual RBBP7 vs RBBP4 contributions in embryonic development not separated\", \"Whether de novo centromere function requires CRL4 activity not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A hemizygous RBBP7 WD40-domain mutation causing loss of histone H4 binding was identified as causing spermatogenic maturation arrest, establishing RBBP7 as a male infertility gene with WD40 domain integrity essential for germ cell viability across species.\",\n      \"evidence\": \"Human genetic variant identification, in vitro H4 interaction assay, cross-species rescue in Drosophila with wild-type vs mutant RBBP7\",\n      \"pmids\": [\"37843278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which RBBP7-containing complex is required for spermatogenesis not determined\", \"Whether female fertility is affected by RBBP7 loss not addressed in human\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work expanded RBBP7's mechanistic repertoire: it deacetylates the non-histone substrate Acsl4 to regulate ferroptosis, recruits LSD1 to stemness gene promoters to erase H3K9me3, and possesses a Cys97-dependent E3 ligase active site amenable to covalent engagement for targeted protein degradation.\",\n      \"evidence\": \"IP-MS with acetyl-proteomics for Acsl4; ChIP-qPCR and metastasis assays for LSD1 recruitment; chemical proteomics with covalent ynamide probes for E3 ligase activity\",\n      \"pmids\": [\"41478474\", \"40038738\", \"40600340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RBBP7 deacetylates Acsl4 directly or through an associated HDAC not fully resolved\", \"Whether Cys97-dependent E3 activity is physiologically relevant outside TPD applications not shown\", \"LSD1-RBBP7 interaction not validated outside breast cancer context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how RBBP7 is allocated among its many complexes (NuRD, CRL4, CAF-1, SIN3A, CoREST), whether complex-specific post-translational modifications govern this partitioning, and whether its newly identified Cys97-dependent E3 ligase activity operates independently of CRL4.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for RBBP7 complex selectivity determined\", \"RBBP7-specific vs RBBP4-redundant functions not systematically delineated\", \"Comprehensive substrate scope for RBBP7 as CRL4 DCAF not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 6, 7, 13, 14, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 8, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5, 8, 9, 11, 14, 20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5, 6, 7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 9, 10, 14, 15, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5, 6, 14, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 10, 20]}\n    ],\n    \"complexes\": [\n      \"NuRD\",\n      \"CRL4 (CUL4-DDB1-ROC1)\",\n      \"CAF-1\",\n      \"SIN3A/HDAC\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"MTA2\",\n      \"DDB1\",\n      \"CUL4B\",\n      \"DNMT1\",\n      \"LSD1\",\n      \"CENP-A\",\n      \"HUWE1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RBBP7 (RbAp46) is a WD40-repeat histone-binding protein that serves as a shared scaffold subunit within multiple chromatin-regulatory complexes—including NuRD, Sin3-HDAC, PRC2, and CAF-1—where it bridges histone substrates (primarily H4) to enzymes that deacetylate, methylate, or remodel chromatin, thereby mediating transcriptional repression and epigenetic gene regulation [PMID:9150135, PMID:10444591, PMID:12435631]. RBBP7 additionally functions as a DDB1-CUL4-associated factor (DCAF) substrate receptor in CRL4 E3 ubiquitin ligase complexes, directing ubiquitin-dependent CENP-A loading at centromeres and proteasomal degradation of targets such as HUWE1 [PMID:25795299, PMID:29738775]. AMPK-mediated phosphorylation of RBBP7 enhances its inhibitory interaction with DNMT1, coupling metabolic sensing to DNA methylation and mitochondrial biogenesis gene expression [PMID:28143904]. A hemizygous loss-of-function variant in X-linked RBBP7 that disrupts histone H4 binding causes maturation arrest azoospermia in humans, with cross-species rescue confirming a cell-autonomous requirement in germ cell survival [PMID:37843278].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The identification of RBBP7 as the histone-binding subunit that tethers the mSin3–HDAC1/2 co-repressor complex to chromatin established its foundational role as a histone chaperone bridging enzymes to their nucleosomal substrates.\",\n      \"evidence\": \"Biochemical purification and co-immunoprecipitation of the mSin3 complex from mammalian cells with functional transcription repression assays\",\n      \"pmids\": [\"9150135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RBBP7–histone H4 interaction was not resolved\", \"Whether RBBP7 contributes catalytic selectivity versus mere tethering was unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that RBBP7 is a core subunit shared between the NuRD and Sin3-HDAC complexes—and not exclusive to one—reframed it as a general-purpose HDAC-delivery module used by multiple remodeling machines.\",\n      \"evidence\": \"Biochemical purification and mass spectrometry of the NuRD complex from multiple labs, showing RBBP7/RBBP4 as shared HDAC core components\",\n      \"pmids\": [\"10444591\", \"9885572\", \"9804427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specificity among NuRD versus Sin3 is achieved despite shared RBBP7 remained unknown\", \"Stoichiometry within each complex was unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The discovery that RBBP7 is an integral subunit of PRC2 with histone H3K27/K9 methyltransferase activity extended its functional repertoire beyond deacetylation to histone methylation-mediated Polycomb silencing.\",\n      \"evidence\": \"Biochemical reconstitution of PRC2 and in vitro HMT assay with SET-domain mutagenesis\",\n      \"pmids\": [\"12435631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RBBP7 contributes allosterically to PRC2 catalysis or acts solely as a histone-presenting platform was not distinguished\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"RNAi depletion of the Drosophila ortholog p55 revealed that RBBP7 is selectively required for RBF/E2F2-mediated repression of differentiation genes but dispensable for E2F1-driven proliferation targets, establishing functional specificity in gene repression.\",\n      \"evidence\": \"RNAi knockdown in Drosophila cells with RT-PCR of specific E2F target gene classes\",\n      \"pmids\": [\"15456884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing RBBP7-dependent from RBBP7-independent E2F repression was not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking RBBP7 to chromosome segregation fidelity, its depletion during oocyte maturation impaired histone deacetylation, chromosomal passenger complex localization, and spindle checkpoint function, causing aneuploidy.\",\n      \"evidence\": \"siRNA/morpholino knockdown in mouse oocytes with immunofluorescence of CPC components and chromosome segregation analysis\",\n      \"pmids\": [\"24317350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HDAC-containing complex mediates the maturation-specific deacetylation was not determined\", \"Whether RBBP7 acts independently of RBBP4 in this context was unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"RBBP7 was shown to function as a DCAF substrate receptor in CRL4 E3 ubiquitin ligase complexes required for ubiquitin-dependent CENP-A loading at centromeres during G1, revealing an unexpected non-chromatin-remodeling role in centromere maintenance.\",\n      \"evidence\": \"RNAi depletion with quantitative CENP-A imaging and biochemical co-immunoprecipitation of CRL4 components in human cells\",\n      \"pmids\": [\"25795299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct ubiquitination substrate at centromeres was not identified\", \"Whether the CRL4-RBBP7 complex has substrates beyond CENP-A loading remained open\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cross-species conservation of RBBP7's centromere function was established when C. elegans LIN-53 depletion phenocopied CENP-A mislocalization and chromosome missegregation at holocentromeres, independent of known chromatin-modifying activities.\",\n      \"evidence\": \"RNAi in C. elegans with immunofluorescence and epistasis analysis with KNL-2 and CENP-A\",\n      \"pmids\": [\"26904949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular mechanism by which RBBP7 promotes CENP-A deposition independently of its HDAC/PRC2 roles was not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"AMPK was identified as a direct kinase for RBBP7, and phosphorylation enhanced RBBP7's inhibitory interaction with DNMT1, establishing a signaling axis from metabolic sensing through epigenetic modification to mitochondrial gene expression.\",\n      \"evidence\": \"Biochemical phosphorylation assay, co-immunoprecipitation, pharmacological AMPK activation in HUVECs, and AMPK-knockout mouse aorta studies\",\n      \"pmids\": [\"28143904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific phosphorylation sites were not mapped at single-residue resolution\", \"Whether AMPK-phosphorylated RBBP7 is selectively excluded from NuRD/PRC2 was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"RBBP7's DCAF function was extended to proteasomal degradation of HUWE1 via CRL4B, with downstream consequences for MCL-1 and BRCA1 stability, linking RBBP7 to apoptotic and DNA damage response regulation through ubiquitin-dependent proteolysis.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, reciprocal overexpression/depletion of RBBP7 with monitoring of HUWE1, MCL-1, and BRCA1 protein levels\",\n      \"pmids\": [\"29738775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding not yet independently confirmed\", \"Whether RBBP7's CRL4 adaptor role extends to additional substrates was not explored systematically\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Redundancy between RBBP7 and RBBP4 was resolved by showing that double, but not single, knockdown causes embryonic lethality at the morula-to-blastocyst transition with aberrant H3.3 deposition and hyperacetylation, revealing compensatory roles in restricting variant histone incorporation during preimplantation development.\",\n      \"evidence\": \"siRNA knockdown in mouse embryos with RNA-seq, ChIP-seq for H3.3 and H3K27ac, and immunofluorescence\",\n      \"pmids\": [\"34709113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3.3 accumulation is a direct consequence of RBBP4/7 loss or secondary to HDAC/PRC2 dysfunction was not distinguished\", \"Individual contributions of RBBP7 versus RBBP4 at specific loci remain unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A hemizygous loss-of-function RBBP7 variant causing maturation arrest azoospermia in humans provided definitive genetic evidence that histone H4 binding by the sixth WD40 domain is essential for germ cell survival, confirmed by cross-species rescue in Drosophila.\",\n      \"evidence\": \"Human genetic variant identification, disrupted RBBP7–H4 co-immunoprecipitation, siRNA in spermatogonial cells, Drosophila germ-cell-specific knockdown with transgenic rescue by wild-type but not mutant human RBBP7\",\n      \"pmids\": [\"37843278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which chromatin complex is critically disrupted in germ cells was not determined\", \"Whether female fertility is similarly affected by RBBP7 hemizygosity is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBBP7 was found to recruit LSD1 to stemness gene promoters in breast cancer, erasing H3K9me3 to activate SOX2/SOX9/OCT4 transcription, and separately to mediate deacetylation of the non-histone substrate Acsl4, enhancing ferroptosis in ovarian aging—expanding its functional scope to demethylation recruitment and non-histone substrate regulation.\",\n      \"evidence\": \"ChIP-qPCR, CRISPR super-enhancer deletion, PDX/PDO models for stemness; IP-MS, acetyl-proteomics, and ferroptosis assays for Acsl4 deacetylation\",\n      \"pmids\": [\"40038738\", \"41478474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RBBP7 recruits LSD1 independently of NuRD is not resolved\", \"The deacetylase that RBBP7 recruits to Acsl4 was not identified\", \"Both findings from single labs await independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include which specific complex contexts mediate RBBP7's distinct functions (centromere assembly, germ cell survival, ferroptosis), how post-translational modifications partition RBBP7 among competing complexes, and whether a high-resolution structure of full-length RBBP7 within NuRD or CRL4 can explain its multivalent substrate recognition.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution cryo-EM structure of RBBP7 within intact NuRD or CRL4 complex\", \"Post-translational modification map (beyond AMPK phosphorylation) not systematically determined\", \"Relative contribution of RBBP7 versus RBBP4 in individual complex contexts remains unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 6, 11, 15, 21, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 14, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 6, 10, 11, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [11, 12, 15, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 6, 11, 20, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 14, 23]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 12, 15, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 18, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 7, 22]}\n    ],\n    \"complexes\": [\n      \"NuRD\",\n      \"Sin3-HDAC\",\n      \"PRC2\",\n      \"CRL4\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"HDAC2\",\n      \"MTA2\",\n      \"DDB1\",\n      \"CUL4B\",\n      \"DNMT1\",\n      \"LSD1\",\n      \"CENP-A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}