{"gene":"RBBP7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"RbAp46 (RBBP7) is a transcriptional target of Wilms' tumor suppressor WT1; WT1 upregulates RbAp46 ~15-fold, and RbAp46 overexpression inhibits cell growth and colony formation, establishing it as a growth inhibitor downstream of WT1.","method":"Suppression subtractive hybridization PCR to identify WT1 target genes; transfection of RbAp46 cDNA with colony formation and growth rate assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified as direct WT1 transcriptional target with functional growth assay readout, single lab, two orthogonal methods","pmids":["9765217"],"is_preprint":false},{"year":2001,"finding":"RbAp46 (RBBP7) interacts specifically with the BRCT domain of BRCA1 via its first two WD-repeats; this interaction represses BRCA1-mediated transactivation of the p21 promoter, and is disrupted by DNA-damaging agents.","method":"Yeast two-hybrid screening; co-immunoprecipitation; luciferase reporter assay for p21 promoter transactivation; domain mapping by deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus reporter assay plus domain mutagenesis, single lab","pmids":["11394910"],"is_preprint":false},{"year":2001,"finding":"RbAp46 (RBBP7) overexpression in adenovirus-transformed HEK293 cells suppresses clonal growth in soft agar and tumor growth in nude mice, increases G2/M fraction, and augments apoptosis under serum starvation, indicating a role in cell cycle control and apoptosis.","method":"Stable transfection; soft agar colony formation; nude mouse xenograft; flow cytometry cell cycle analysis; serum starvation apoptosis assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in vitro and in vivo, single lab","pmids":["11433396"],"is_preprint":false},{"year":2003,"finding":"Inducible RbAp46 expression activates the JNK (c-Jun NH2-terminal kinase) signaling pathway and triggers apoptosis; a dominant-negative JNK1 mutant blocks RbAp46-mediated apoptosis, placing RbAp46 upstream of JNK in this pathway.","method":"Tetracycline-inducible expression system; JNK activity assay; dominant-negative JNK1 epistasis; tumor xenograft in nude mice","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with dominant-negative mutant plus in vivo validation, single lab","pmids":["14981905"],"is_preprint":false},{"year":2003,"finding":"Overexpression of RbAp46 in neoplastigenic MCF10AT3B breast epithelial cells constitutively activates the JNK pathway and GADD45, sensitizing cells to apoptosis induced by serum deprivation and hydrocortisone withdrawal.","method":"Stable cell line establishment; soft agar colony formation; nude mouse xenograft; Western blot for JNK and GADD45 activation","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple phenotypic assays with pathway readout, single lab","pmids":["12767060"],"is_preprint":false},{"year":2004,"finding":"Drosophila p55 (ortholog of RbAp46/RbAp48/RBBP7) is essential for repression of dE2F2-regulated target genes by the pRB-related proteins RBF1 and RBF2; its depletion deregulates E2F targets in a cell cycle-independent manner without affecting proliferation-coupled E2F targets, indicating mechanistically distinct repression modes.","method":"RNAi depletion of p55 in Drosophila cells; RT-PCR and reporter assays for E2F target gene expression; genetic epistasis with dE2F2/RBF complexes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic RNAi epistasis screen with multiple E2F target readouts, clear mechanistic pathway placement, ortholog study directly inferring mammalian RbAp46 function","pmids":["15456884"],"is_preprint":false},{"year":2006,"finding":"RbAp46 expression in mammary epithelial cells upregulates GSK-3β expression, leading to increased phosphorylation and reduced steady-state levels of β-catenin and decreased β-catenin/TCF nuclear signaling.","method":"Stable cell line expressing RbAp46; Western blot for β-catenin phosphorylation and GSK-3β; TCF luciferase reporter assay; cell growth assay","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single luciferase and Western blot approach, no direct mechanistic link established between RBBP7 and GSK-3β","pmids":["17201172"],"is_preprint":false},{"year":2006,"finding":"Constitutive RbAp46 expression in MCF10AT3B mammary epithelial cells induces epithelial-mesenchymal transition (EMT), characterized by downregulation of epithelial markers, upregulation of mesenchymal markers, and increased migration and invasion.","method":"Western blot and immunofluorescence for EMT markers; migration and invasion assays (Transwell)","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, descriptive phenotype with marker readout, no direct molecular mechanism for how RBBP7 drives EMT","pmids":["17094482"],"is_preprint":false},{"year":2008,"finding":"SUMO-1 physically interacts with RbAp46 and co-localizes in the nucleus; SUMO-1 overexpression increases RbAp46 protein stability (not at the transcriptional level and not via sumoylation of RbAp46), and this stabilization enhances RbAp46-mediated suppression of Ras-driven cell growth.","method":"Co-immunoprecipitation; co-localization by immunofluorescence; Western blot for protein levels with transcription and degradation controls; cell growth assay","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP plus co-localization plus protein stability analysis ruling out transcriptional/degradation mechanism, single lab","pmids":["19189660"],"is_preprint":false},{"year":2015,"finding":"RbAp46 (RBBP7) binds with HDAC1 and Sp1, and this complex binds to the RECK promoter at the Sp1 site, repressing RECK expression; Ras upregulates RbAp46 to suppress RECK and increase MMP-9 activity, promoting metastasis.","method":"Chromatin immunoprecipitation (ChIP); DNA affinity precipitation assay (DAPA); RECK reporter gene assay; lentiviral shRNA knockdown; xenograft lung metastasis model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and DAPA directly show promoter binding, reporter assay and in vivo metastasis model, single lab with multiple methods","pmids":["25885317"],"is_preprint":false},{"year":2015,"finding":"RBBP7 is a substrate-specific adaptor (DCAF) for the CRL4 E3 ubiquitin ligase complex (CUL4/DDB1/ROC1); as CRL4(RBBP7), it is required for centromeric loading of newly synthesized CENP-A during G1 phase, in addition to binding and stabilizing soluble CENP-A.","method":"Biochemical fractionation; quantitative imaging; RNAi depletion of CUL4, DDB1, and RBBP7; CENP-A localization assays by fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical and imaging methods, systematic depletion of complex components, single lab","pmids":["25795299"],"is_preprint":false},{"year":2015,"finding":"Rbbp7 knockdown in mouse oocytes prevents maturation-associated histone deacetylation, which in turn disrupts chromosomal passenger complex (CPC) localization and function, leading to chromosome misalignment, improper kinetochore-microtubule attachments, impaired spindle assembly checkpoint, cytokinesis defects, and aneuploidy at metaphase II.","method":"siRNA/morpholino knockdown; Western blot for histone acetylation; immunofluorescence for CPC components; kinetochore-microtubule attachment assays; spindle assembly checkpoint assay; aneuploidy scoring","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods linking RBBP7 to histone deacetylation to CPC function with clearly defined cellular phenotypes, replicated across multiple readouts","pmids":["24317350"],"is_preprint":false},{"year":2015,"finding":"Rbbp7 silencing in mouse uterine stromal cells attenuates histone H4 acetylation and reduces cyclin D3 expression, compromising stromal cell decidualization; Rbbp7 expression is induced by progesterone/nuclear receptor PR signaling.","method":"In situ hybridization; immunochemistry; stealth RNA knockdown; primary murine uterine stromal cell culture; in vitro decidualization model; Western blot","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined molecular readouts (H4 acetylation, cyclin D3) plus upstream PR signaling demonstration, single lab","pmids":["26040671"],"is_preprint":false},{"year":2016,"finding":"C. elegans RbAp46/48 (LIN-53, ortholog of RBBP7) is required for CENP-A(HCP-3) localization at holocentromeres; LIN-53 and CENP-A localizations are interdependent, and LIN-53 localization at the centromere during metaphase requires both CENP-A(HCP-3) and M18BP1(KNL-2). This function is independent of histone acetylation, H3K27 trimethylation, or known chromatin-modifying complexes.","method":"RNAi depletion; immunofluorescence for CENP-A and kinetochore components; epistasis analysis with KNL-2; anaphase bridge and chromosome missegregation scoring","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic epistasis analysis with multiple markers, negative controls ruling out known complexes, replicated across multiple assays in ortholog system","pmids":["26904949"],"is_preprint":false},{"year":2017,"finding":"AMPK directly phosphorylates RBBP7 at an AMPK consensus sequence; this phosphorylation increases interaction between RBBP7 and DNMT1, contributing to inhibition of DNMT1-mediated DNA methylation and promoting nucleosome remodeling for mitochondrial gene expression.","method":"Identification of AMPK phosphorylation consensus in RBBP7; co-immunoprecipitation showing increased RBBP7-DNMT1 interaction upon AMPK activation; pharmacological AMPK activation in HUVECs and mouse aorta; methylation assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical phosphorylation identification plus co-IP showing functional consequence, multiple cell and in vivo models, single lab","pmids":["28143904"],"is_preprint":false},{"year":2017,"finding":"The human MTA2-RBBP7 sub-complex of the NuRD complex can be isolated as a stable complex in vitro; negative stain electron microscopy reveals an elongated architecture with hinge-like motion, consistent with the 2:4 stoichiometry (MTA:RBBP) seen in Drosophila NuRD.","method":"Recombinant expression in HEK293F cells; affinity purification; negative stain electron microscopy and 3D reconstruction","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural characterization by EM with biochemical reconstitution, single lab, limited functional validation","pmids":["28179136"],"is_preprint":false},{"year":2018,"finding":"RBBP7 functions as the DCAF substrate receptor in the CRL4B (DDB1-CUL4B-ROC1) E3 ubiquitin ligase complex, bridging the complex to HUWE1 and mediating its polyubiquitination and proteasomal degradation; RBBP7 depletion stabilizes HUWE1 and accelerates degradation of MCL-1 and BRCA1 (HUWE1 substrates).","method":"Co-immunoprecipitation; ubiquitination assay in vitro and in cells; RBBP7 overexpression and depletion with Western blot for HUWE1, MCL-1, and BRCA1 levels","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus gain/loss of function ubiquitination assays with substrate-level readout, single lab","pmids":["29738775"],"is_preprint":false},{"year":2021,"finding":"Double knockdown of Rbbp4 and Rbbp7 (but not individual knockdowns) causes embryonic lethality at the morula-to-blastocyst transition in mice, with cell cycle block, disrupted lineage specification, and a dramatic increase in H3.3 and H3K27ac abundance; ChIP-seq reveals H3.3 enrichment at promoters of RBBP4/7 target genes, indicating compensatory roles in H3.3 deposition and chromatin regulation.","method":"siRNA double knockdown in preimplantation embryos; ChIP-seq for H3.3 and H3K27ac; RNA-seq for gene expression; immunofluorescence for lineage markers","journal":"Epigenetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with genome-wide ChIP-seq and RNA-seq, multiple orthogonal readouts establishing mechanistic role in H3.3 deposition","pmids":["34709113"],"is_preprint":false},{"year":2021,"finding":"Rbbp7 overexpression in hippocampal neurons reduces p300 levels, decreases tau acetylation at lysine 280, and reduces tau phosphorylation at AT8 and AT100 sites, thereby protecting against tau-induced neuronal death; in vitro Rbbp7 overexpression rescues TauP301L-induced cytotoxicity.","method":"Rbbp7 viral overexpression in PS19 mouse hippocampus; Western blot for p300, tau acetylation, and phosphorylation; neuronal survival quantification in CA1; cell viability assays in immortalized hippocampal cells and primary cortical neurons","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss/gain of function with multiple molecular readouts linking RBBP7 to p300 and tau modification, single lab","pmids":["33978814"],"is_preprint":false},{"year":2021,"finding":"C. elegans RbAp46/48 (LIN-53) and HAT-1 are required for de novo CENP-A(HCP-3) and Mis18BP1(KNL-2) initial deposition at newly formed centromeres on artificial chromosomes; this requirement differs from centromere maintenance on endogenous chromosomes where KNL-2 acts upstream of LIN-53.","method":"RNAi depletion; microinjection of artificial chromosome constructs; immunofluorescence for CENP-A, KNL-2, and acetylation marks; epistasis analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic epistasis with multiple centromere assembly factors, de novo vs maintenance distinction established, ortholog study with mechanistic resolution","pmids":["33872374"],"is_preprint":false},{"year":2023,"finding":"A hemizygous truncating mutation in RBBP7 (affecting the sixth WD40 domain) abrogates interaction with histone H4 and causes maturation arrest in spermatogenesis; Drosophila Caf1-55 (RBBP7 ortholog) knockdown in germ cells eliminates germ cells, while knockdown in cyst cells causes hyperproliferative testicular cells, and male infertility is rescued by wild-type human RBBP7 but not mutant variants.","method":"Human genetic variant identification; domain mapping by mutation analysis; Co-IP for histone H4 interaction; γH2AX and BRCA1 Western blot; Drosophila germline-specific and cyst cell-specific RNAi; rescue with wild-type vs. mutant human RBBP7","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic variant with domain-level functional mapping, cross-species rescue experiment with mutant vs. WT, multiple cellular readouts","pmids":["37843278"],"is_preprint":false},{"year":2024,"finding":"SP1 transcription factor directly activates the RBBP7 promoter; RBBP7 in turn activates PI3K/AKT signaling to promote glycolysis (Warburg effect) and hepatocellular carcinoma cell proliferation.","method":"Dual-luciferase reporter assay for SP1-RBBP7 promoter; chromatin immunoprecipitation; Western blot for PI3K/AKT phosphorylation; CCK8 and colony formation; measurement of glycolytic enzymes and metabolites","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase directly confirm SP1-RBBP7 promoter interaction; PI3K/AKT activation established by phosphorylation assay; single lab","pmids":["38368381"],"is_preprint":false},{"year":2025,"finding":"RBBP7 functions as a novel E3 ubiquitin ligase via covalent engagement at Cys97; ynamide-containing small-molecule degraders covalently engage Cys97 of RBBP7 to recruit it as the E3 ligase responsible for targeted degradation of multiple proteins including CDK4, PDE5, PI3K, AKT, BRD4, and mutant EGFR.","method":"Chemical proteomics (activity-based protein profiling); proteome profiling after degrader treatment; covalent labeling with ynamide electrophile; functional validation of target degradation by Western blot; site-specific mutagenesis (Cys97)","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics with covalent site identification and functional degradation validation, single lab, novel mechanism","pmids":["40600340"],"is_preprint":false},{"year":2025,"finding":"RBBP7 directly deacetylates Acsl4 at lysine 401, reducing Acsl4 acetylation; deacetylation of Acsl4-K401 increases its enzyme activity by promoting ATP binding, thereby enhancing ferroptosis and promoting ovarian aging.","method":"Acetyl-proteomics; immunoprecipitation-mass spectrometry (IP-MS) identifying RBBP7 as direct Acsl4 deacetylation mediator; site-specific acetylation mutant analysis; Acsl4 enzyme activity assay; ferroptosis assays in vivo and in vitro","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification plus site-specific mutagenesis with enzyme activity readout; single lab; novel deacetylase substrate role","pmids":["41478474"],"is_preprint":false},{"year":2025,"finding":"RBBP7 interacts with LSD1 and recruits it to promoters of stemness genes (SOX9, SOX2, OCT4, CCND1) to erase repressive H3K9me3 marks, transcriptionally upregulating stemness gene expression and promoting breast cancer stem-like properties and metastasis.","method":"Co-immunoprecipitation for RBBP7-LSD1 interaction; ChIP-qPCR for H3K9me3 and LSD1 at stemness gene promoters; CRISPR/Cas9 deletion of RBBP7 super-enhancer; tumor sphere formation; tail vein metastasis model; PDO and PDX models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP-qPCR with in vivo validation and CRISPR genetic tools, single lab, multiple orthogonal methods","pmids":["40038738"],"is_preprint":false}],"current_model":"RBBP7 (RbAp46) is a WD40-repeat histone chaperone and chromatin adaptor that operates as a shared subunit of multiple chromatin-modifying complexes (NuRD, SIN3A, CoREST, CAF-1, CRL4); it facilitates histone deacetylation (as part of NuRD/HDAC complexes), mediates CENP-A deposition at centromeres as a substrate adaptor of CRL4 E3 ligase, directly deacetylates non-histone substrates (e.g., Acsl4-K401), targets HUWE1 for ubiquitin-proteasomal degradation via CRL4B, recruits LSD1 to erase repressive chromatin marks at stemness gene promoters, interacts with BRCA1-BRCT to modulate transcriptional activity, binds DNMT1 upon AMPK-mediated phosphorylation to inhibit DNA methylation, and is phosphorylated by AMPK to regulate nucleosome remodeling; its histone H4-binding function (via WD40 domains) is essential for spermatogenesis and proper chromosome segregation during meiosis and mitosis."},"narrative":{"mechanistic_narrative":"RBBP7 (RbAp46) is a WD40-repeat histone chaperone and chromatin adaptor that serves as a shared subunit of histone-modifying machinery and links chromatin regulation to cell-cycle control, chromosome segregation, and gene expression [PMID:24317350, PMID:28179136]. Through its WD40 domains it binds histone H4, and this histone-binding function — abolished by a truncating mutation in the sixth WD40 domain — is essential for spermatogenesis, with male infertility rescued by wild-type but not mutant human RBBP7 [PMID:37843278]. As part of histone deacetylase machinery it drives maturation-associated histone deacetylation required for chromosomal passenger complex localization and faithful meiotic chromosome segregation in oocytes [PMID:24317350], while RBBP7 together with its paralog supports H3.3 deposition and chromatin regulation during preimplantation development [PMID:34709113]. RBBP7 acts as the substrate-receptor (DCAF) subunit of CRL4 ubiquitin ligase complexes: as CRL4(RBBP7) it stabilizes soluble CENP-A and mediates its centromeric loading [PMID:25795299], and as CRL4B it bridges and degrades HUWE1, thereby controlling MCL-1 and BRCA1 levels [PMID:29738775]; orthologs are likewise required for CENP-A deposition at centromeres [PMID:26904949, PMID:33872374]. Beyond chromatin, RBBP7 is phosphorylated by AMPK, which enhances its interaction with DNMT1 to inhibit DNA methylation and remodel nucleosomes [PMID:28143904], recruits LSD1 to erase repressive H3K9me3 at stemness gene promoters [PMID:40038738], and directly deacetylates the non-histone substrate Acsl4 at K401 to modulate its enzyme activity and ferroptosis [PMID:41478474]. RBBP7 also functions in transcriptional regulation through interactions with BRCA1-BRCT [PMID:11394910] and HDAC1/Sp1 at target promoters [PMID:25885317], and its expression-level changes modulate growth, apoptosis, and JNK signaling [PMID:9765217, PMID:15456884].","teleology":[{"year":1998,"claim":"Established RBBP7 as a growth-regulatory gene downstream of a tumor suppressor, providing the first functional context for the protein.","evidence":"Suppression subtractive hybridization identifying RbAp46 as a WT1 target, with colony formation and growth assays","pmids":["9765217"],"confidence":"Medium","gaps":["Did not define the molecular mechanism of growth inhibition","WT1-dependence shown but RBBP7 biochemical activity not addressed"]},{"year":2001,"claim":"Connected RBBP7 to transcriptional regulation and DNA-damage signaling by mapping a WD-repeat-dependent interaction with the BRCA1 BRCT domain that represses p21 transactivation.","evidence":"Yeast two-hybrid, co-IP, luciferase reporter and deletion mapping","pmids":["11394910"],"confidence":"Medium","gaps":["Functional consequence at endogenous BRCA1 targets genome-wide unknown","Mechanism of disruption by DNA damage not resolved"]},{"year":2003,"claim":"Linked RBBP7 overexpression to apoptotic and tumor-suppressive output via the JNK/GADD45 pathway, placing it upstream of a stress-signaling cascade.","evidence":"Inducible expression, JNK activity assays, dominant-negative JNK1 epistasis, xenografts (idx 2,3,4)","pmids":["11433396","14981905","12767060"],"confidence":"Medium","gaps":["How a chromatin adaptor activates JNK is not mechanistically defined","Overexpression phenotypes may not reflect endogenous function"]},{"year":2004,"claim":"Used the Drosophila ortholog p55 to place RBBP7 in pRB/E2F transcriptional repression, distinguishing cell-cycle-independent from proliferation-coupled repression modes.","evidence":"RNAi depletion of p55 with E2F target RT-PCR/reporter assays and RBF complex epistasis","pmids":["15456884"],"confidence":"High","gaps":["Direct mammalian validation not performed in this study","Which complexes mediate each repression mode not delineated"]},{"year":2015,"claim":"Defined RBBP7 as a substrate-specific adaptor (DCAF) of CRL4 required for centromeric loading and stabilization of CENP-A, giving it a defined enzymatic-complex role in centromere identity.","evidence":"Biochemical fractionation, quantitative imaging, RNAi of CUL4/DDB1/RBBP7 with CENP-A localization assays","pmids":["25795299"],"confidence":"Medium","gaps":["Ubiquitination target relevant to CENP-A loading not identified","Structural basis of CENP-A recognition unresolved"]},{"year":2015,"claim":"Demonstrated that RBBP7-dependent histone deacetylation governs chromosomal passenger complex function and accurate chromosome segregation in oocytes, tying its chromatin role to meiotic fidelity.","evidence":"siRNA/morpholino knockdown in mouse oocytes with histone acetylation Western, CPC immunofluorescence, kinetochore-microtubule and SAC assays","pmids":["24317350"],"confidence":"High","gaps":["Which HDAC complex mediates the relevant deacetylation not specified","Direct CPC-RBBP7 link not established"]},{"year":2015,"claim":"Extended RBBP7's chromatin-deacetylation role to reproductive tissue, showing it supports H4 acetylation-dependent cyclin D3 expression and decidualization under progesterone control.","evidence":"RNA knockdown in murine uterine stromal cells with H4 acetylation and cyclin D3 readouts and PR signaling demonstration","pmids":["26040671"],"confidence":"Medium","gaps":["Direct chromatin targets at the cyclin D3 locus not mapped","Complex context for the acetylation effect unclear"]},{"year":2015,"claim":"Placed RBBP7 in an HDAC1/Sp1 promoter-bound repressor complex controlling RECK and metastasis, connecting it to Ras-driven invasion.","evidence":"ChIP, DAPA, RECK reporter, shRNA knockdown and xenograft lung metastasis model","pmids":["25885317"],"confidence":"Medium","gaps":["Whether this complex is canonical NuRD/Sin3 not defined","Direct vs. indirect Ras regulation of RBBP7 unresolved"]},{"year":2016,"claim":"Showed the centromere-loading function of RBBP7 orthologs can be independent of histone acetylation and known chromatin complexes, revealing a chaperone activity distinct from its HDAC-complex roles.","evidence":"RNAi and epistasis with CENP-A(HCP-3) and KNL-2 in C. elegans holocentromeres","pmids":["26904949"],"confidence":"High","gaps":["Molecular basis of acetylation-independent CENP-A handoff unknown","Direct mammalian confirmation of independence not shown"]},{"year":2017,"claim":"Identified AMPK as an upstream kinase that phosphorylates RBBP7 to enhance DNMT1 binding and inhibit DNA methylation, integrating metabolic signaling with chromatin/DNA-methylation control.","evidence":"Consensus-site identification, co-IP upon AMPK activation, pharmacological AMPK activation in HUVECs/mouse aorta and methylation assays","pmids":["28143904"],"confidence":"Medium","gaps":["Phosphosite mutagenesis validation not detailed","Genome-wide methylation consequences not mapped"]},{"year":2017,"claim":"Provided structural insight into RBBP7 within NuRD by reconstituting and imaging the MTA2-RBBP7 sub-complex, defining its stoichiometry and architecture.","evidence":"Recombinant expression, affinity purification and negative stain EM 3D reconstruction","pmids":["28179136"],"confidence":"Medium","gaps":["High-resolution structure not obtained","Functional consequence of the hinge motion untested"]},{"year":2018,"claim":"Defined a second CRL4-based role, with RBBP7 acting as the CRL4B DCAF that ubiquitinates HUWE1 and thereby controls MCL-1 and BRCA1 stability, expanding its E3-adaptor function to apoptosis and DNA-damage proteins.","evidence":"Co-IP, in vitro and cellular ubiquitination assays, gain/loss of function with HUWE1/MCL-1/BRCA1 Western blots","pmids":["29738775"],"confidence":"Medium","gaps":["Structural basis of HUWE1 recognition unknown","Physiological contexts requiring this axis not delineated"]},{"year":2021,"claim":"Revealed paralog redundancy in development, with combined Rbbp4/Rbbp7 loss causing peri-implantation lethality and aberrant H3.3/H3K27ac, implicating RBBP7 in H3.3 deposition.","evidence":"siRNA double knockdown in mouse embryos with ChIP-seq, RNA-seq and lineage marker immunofluorescence","pmids":["34709113"],"confidence":"High","gaps":["Direct biochemical role in H3.3 chaperoning not isolated from paralog","Which complex mediates the embryonic function unclear"]},{"year":2021,"claim":"Demonstrated a neuroprotective role through RBBP7-mediated reduction of p300 and tau acetylation/phosphorylation, extending its regulation of acetylation machinery to neurodegeneration.","evidence":"Viral overexpression in PS19 hippocampus and TauP301L cells with Western blot and survival/viability assays","pmids":["33978814"],"confidence":"Medium","gaps":["Mechanism by which RBBP7 lowers p300 not defined","Direct vs. indirect effect on tau modification unresolved"]},{"year":2021,"claim":"Distinguished de novo from maintenance centromere assembly, showing RBBP7 ortholog and HAT-1 are needed for initial CENP-A deposition on artificial chromosomes versus a KNL-2-upstream maintenance pathway.","evidence":"RNAi, artificial chromosome microinjection and epistasis with CENP-A/KNL-2 in C. elegans","pmids":["33872374"],"confidence":"High","gaps":["Mechanistic role of acetylation (HAT-1) in initial deposition not fully resolved","Mammalian de novo centromere relevance untested"]},{"year":2023,"claim":"Established the WD40-H4 binding function of RBBP7 as essential for human spermatogenesis through a causative truncating mutation and cross-species rescue, providing a direct disease link.","evidence":"Human variant identification, domain mapping, H4 co-IP, and Drosophila germline/cyst-cell RNAi with WT-vs-mutant human RBBP7 rescue","pmids":["37843278"],"confidence":"High","gaps":["Downstream chromatin events in arresting spermatocytes not detailed","Penetrance and broader phenotype spectrum not established"]},{"year":2024,"claim":"Connected RBBP7 to oncogenic metabolism, showing SP1 drives RBBP7 expression to activate PI3K/AKT and the Warburg effect in hepatocellular carcinoma.","evidence":"Luciferase, ChIP, PI3K/AKT phosphorylation Western, proliferation and glycolysis assays","pmids":["38368381"],"confidence":"Medium","gaps":["Mechanism linking RBBP7 to PI3K/AKT not defined","Direct vs. transcriptional effect unresolved"]},{"year":2025,"claim":"Uncovered new catalytic and adaptor activities: a covalently druggable Cys97 conferring E3-ligase-like degradation of diverse targets, a direct deacetylase role toward Acsl4-K401, and LSD1 recruitment to demethylate stemness gene promoters.","evidence":"Chemical proteomics with Cys97 mutagenesis (idx 22); acetyl-proteomics/IP-MS with Acsl4 mutant and activity assays (idx 23); co-IP and ChIP-qPCR with CRISPR and in vivo models (idx 24)","pmids":["40600340","41478474","40038738"],"confidence":"Medium","gaps":["Whether endogenous RBBP7 acts as a bona fide E3 ligase outside engineered degraders unclear","Direct deacetylase catalytic mechanism for a WD40 protein not structurally resolved","Specificity determinants for LSD1 recruitment unmapped"]},{"year":null,"claim":"How RBBP7's distinct activities — histone H4 chaperoning, HDAC-complex deacetylation, CRL4 substrate adaptation, AMPK-regulated DNMT1 binding, and the newly reported intrinsic deacetylase/E3 activities — are partitioned and regulated within a single WD40 protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model reconciling chaperone vs. catalytic claims","Cell-type and complex context dictating which activity dominates not defined","Endogenous (non-engineered) catalytic activities require independent confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[11,15,20]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,16,23]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,9,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[16,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,15]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,13]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,15,17,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,11,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,16]}],"complexes":["NuRD (MTA2-RBBP7)","CRL4(RBBP7) / CRL4B E3 ubiquitin ligase","HDAC1/Sp1 promoter complex"],"partners":["BRCA1","HDAC1","DNMT1","HUWE1","LSD1","MTA2","CENP-A","HISTONE H4"],"other_free_text":[]}},"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 Classified","n_dependent_lines":119,"n_total_lines":1208,"dependency_fraction":0.09850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H2AFZ","stoichiometry":10.0},{"gene":"HDAC1","stoichiometry":10.0},{"gene":"RBBP4","stoichiometry":10.0},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RBBP7","total_profiled":1310},"omim":[{"mim_id":"621297","title":"LYMPHATIC ENDOTHELIAL TRANSCRIPTIONAL REGULATOR lncRNA 1; LETR1","url":"https://www.omim.org/entry/621297"},{"mim_id":"614998","title":"GATA ZINC FINGER DOMAIN-CONTAINING PROTEIN 2B; GATAD2B","url":"https://www.omim.org/entry/614998"},{"mim_id":"605984","title":"EMBRYONIC ECTODERM DEVELOPMENT; EED","url":"https://www.omim.org/entry/605984"},{"mim_id":"605164","title":"HISTONE DEACETYLASE 2; HDAC2","url":"https://www.omim.org/entry/605164"},{"mim_id":"603947","title":"METASTASIS-ASSOCIATED PROTEIN 2; MTA2","url":"https://www.omim.org/entry/603947"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBBP7"},"hgnc":{"alias_symbol":["RbAp46"],"prev_symbol":[]},"alphafold":{"accession":"Q16576","domains":[{"cath_id":"2.130.10.10","chopping":"132-408","consensus_level":"medium","plddt":97.2807,"start":132,"end":408}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16576","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16576-F1-predicted_aligned_error_v6.png","plddt_mean":90.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBBP7","jax_strain_url":"https://www.jax.org/strain/search?query=RBBP7"},"sequence":{"accession":"Q16576","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16576"}},"corpus_meta":[{"pmid":"28143904","id":"PMC_28143904","title":"AMPK promotes mitochondrial 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Proteins and proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28179136","citation_count":9,"is_preprint":false},{"pmid":"14981905","id":"PMC_14981905","title":"Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.","date":"2003","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/14981905","citation_count":9,"is_preprint":false},{"pmid":"19189660","id":"PMC_19189660","title":"SUMO-1 overexpression increases RbAp46 protein stability and suppresses cell growth.","date":"2008","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19189660","citation_count":8,"is_preprint":false},{"pmid":"37225855","id":"PMC_37225855","title":"FIT links c-Myc and P53 acetylation by recruiting RBBP7 during colorectal carcinogenesis.","date":"2023","source":"Cancer gene 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40934061","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21646,"output_tokens":6597,"usd":0.081947,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15280,"output_tokens":5774,"usd":0.110375,"stage2_stop_reason":"end_turn"},"total_usd":0.192322,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"RbAp46 (RBBP7) is a transcriptional target of Wilms' tumor suppressor WT1; WT1 upregulates RbAp46 ~15-fold, and RbAp46 overexpression inhibits cell growth and colony formation, establishing it as a growth inhibitor downstream of WT1.\",\n      \"method\": \"Suppression subtractive hybridization PCR to identify WT1 target genes; transfection of RbAp46 cDNA with colony formation and growth rate assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified as direct WT1 transcriptional target with functional growth assay readout, single lab, two orthogonal methods\",\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-repeats; this interaction represses BRCA1-mediated transactivation of the p21 promoter, and is disrupted by DNA-damaging agents.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; luciferase reporter assay for p21 promoter transactivation; domain mapping by deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus reporter assay plus domain mutagenesis, single lab\",\n      \"pmids\": [\"11394910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RbAp46 (RBBP7) overexpression in adenovirus-transformed HEK293 cells suppresses clonal growth in soft agar and tumor growth in nude mice, increases G2/M fraction, and augments apoptosis under serum starvation, indicating a role in cell cycle control and apoptosis.\",\n      \"method\": \"Stable transfection; soft agar colony formation; nude mouse xenograft; flow cytometry cell cycle analysis; serum starvation apoptosis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"11433396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Inducible RbAp46 expression activates the JNK (c-Jun NH2-terminal kinase) signaling pathway and triggers apoptosis; a dominant-negative JNK1 mutant blocks RbAp46-mediated apoptosis, placing RbAp46 upstream of JNK in this pathway.\",\n      \"method\": \"Tetracycline-inducible expression system; JNK activity assay; dominant-negative JNK1 epistasis; tumor xenograft in nude mice\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with dominant-negative mutant plus in vivo validation, single lab\",\n      \"pmids\": [\"14981905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of RbAp46 in neoplastigenic MCF10AT3B breast epithelial cells constitutively activates the JNK pathway and GADD45, sensitizing cells to apoptosis induced by serum deprivation and hydrocortisone withdrawal.\",\n      \"method\": \"Stable cell line establishment; soft agar colony formation; nude mouse xenograft; Western blot for JNK and GADD45 activation\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple phenotypic assays with pathway readout, single lab\",\n      \"pmids\": [\"12767060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila p55 (ortholog of RbAp46/RbAp48/RBBP7) is essential for repression of dE2F2-regulated target genes by the pRB-related proteins RBF1 and RBF2; its depletion deregulates E2F targets in a cell cycle-independent manner without affecting proliferation-coupled E2F targets, indicating mechanistically distinct repression modes.\",\n      \"method\": \"RNAi depletion of p55 in Drosophila cells; RT-PCR and reporter assays for E2F target gene expression; genetic epistasis with dE2F2/RBF complexes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic RNAi epistasis screen with multiple E2F target readouts, clear mechanistic pathway placement, ortholog study directly inferring mammalian RbAp46 function\",\n      \"pmids\": [\"15456884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RbAp46 expression in mammary epithelial cells upregulates GSK-3β expression, leading to increased phosphorylation and reduced steady-state levels of β-catenin and decreased β-catenin/TCF nuclear signaling.\",\n      \"method\": \"Stable cell line expressing RbAp46; Western blot for β-catenin phosphorylation and GSK-3β; TCF luciferase reporter assay; cell growth assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single luciferase and Western blot approach, no direct mechanistic link established between RBBP7 and GSK-3β\",\n      \"pmids\": [\"17201172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Constitutive RbAp46 expression in MCF10AT3B mammary epithelial cells induces epithelial-mesenchymal transition (EMT), characterized by downregulation of epithelial markers, upregulation of mesenchymal markers, and increased migration and invasion.\",\n      \"method\": \"Western blot and immunofluorescence for EMT markers; migration and invasion assays (Transwell)\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, descriptive phenotype with marker readout, no direct molecular mechanism for how RBBP7 drives EMT\",\n      \"pmids\": [\"17094482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUMO-1 physically interacts with RbAp46 and co-localizes in the nucleus; SUMO-1 overexpression increases RbAp46 protein stability (not at the transcriptional level and not via sumoylation of RbAp46), and this stabilization enhances RbAp46-mediated suppression of Ras-driven cell growth.\",\n      \"method\": \"Co-immunoprecipitation; co-localization by immunofluorescence; Western blot for protein levels with transcription and degradation controls; cell growth assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP plus co-localization plus protein stability analysis ruling out transcriptional/degradation mechanism, single lab\",\n      \"pmids\": [\"19189660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RbAp46 (RBBP7) binds with HDAC1 and Sp1, and this complex binds to the RECK promoter at the Sp1 site, repressing RECK expression; Ras upregulates RbAp46 to suppress RECK and increase MMP-9 activity, promoting metastasis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); DNA affinity precipitation assay (DAPA); RECK reporter gene assay; lentiviral shRNA knockdown; xenograft lung metastasis model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and DAPA directly show promoter binding, reporter assay and in vivo metastasis model, single lab with multiple methods\",\n      \"pmids\": [\"25885317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBBP7 is a substrate-specific adaptor (DCAF) for the CRL4 E3 ubiquitin ligase complex (CUL4/DDB1/ROC1); as CRL4(RBBP7), it is required for centromeric loading of newly synthesized CENP-A during G1 phase, in addition to binding and stabilizing soluble CENP-A.\",\n      \"method\": \"Biochemical fractionation; quantitative imaging; RNAi depletion of CUL4, DDB1, and RBBP7; CENP-A localization assays by fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical and imaging methods, systematic depletion of complex components, single lab\",\n      \"pmids\": [\"25795299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rbbp7 knockdown in mouse oocytes prevents maturation-associated histone deacetylation, which in turn disrupts chromosomal passenger complex (CPC) localization and function, leading to chromosome misalignment, improper kinetochore-microtubule attachments, impaired spindle assembly checkpoint, cytokinesis defects, and aneuploidy at metaphase II.\",\n      \"method\": \"siRNA/morpholino knockdown; Western blot for histone acetylation; immunofluorescence for CPC components; kinetochore-microtubule attachment assays; spindle assembly checkpoint assay; aneuploidy scoring\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods linking RBBP7 to histone deacetylation to CPC function with clearly defined cellular phenotypes, replicated across multiple readouts\",\n      \"pmids\": [\"24317350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rbbp7 silencing in mouse uterine stromal cells attenuates histone H4 acetylation and reduces cyclin D3 expression, compromising stromal cell decidualization; Rbbp7 expression is induced by progesterone/nuclear receptor PR signaling.\",\n      \"method\": \"In situ hybridization; immunochemistry; stealth RNA knockdown; primary murine uterine stromal cell culture; in vitro decidualization model; Western blot\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined molecular readouts (H4 acetylation, cyclin D3) plus upstream PR signaling demonstration, single lab\",\n      \"pmids\": [\"26040671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans RbAp46/48 (LIN-53, ortholog of RBBP7) is required for CENP-A(HCP-3) localization at holocentromeres; LIN-53 and CENP-A localizations are interdependent, and LIN-53 localization at the centromere during metaphase requires both CENP-A(HCP-3) and M18BP1(KNL-2). This function is independent of histone acetylation, H3K27 trimethylation, or known chromatin-modifying complexes.\",\n      \"method\": \"RNAi depletion; immunofluorescence for CENP-A and kinetochore components; epistasis analysis with KNL-2; anaphase bridge and chromosome missegregation scoring\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic epistasis analysis with multiple markers, negative controls ruling out known complexes, replicated across multiple assays in ortholog system\",\n      \"pmids\": [\"26904949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK directly phosphorylates RBBP7 at an AMPK consensus sequence; this phosphorylation increases interaction between RBBP7 and DNMT1, contributing to inhibition of DNMT1-mediated DNA methylation and promoting nucleosome remodeling for mitochondrial gene expression.\",\n      \"method\": \"Identification of AMPK phosphorylation consensus in RBBP7; co-immunoprecipitation showing increased RBBP7-DNMT1 interaction upon AMPK activation; pharmacological AMPK activation in HUVECs and mouse aorta; methylation assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical phosphorylation identification plus co-IP showing functional consequence, multiple cell and in vivo models, single lab\",\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 complex in vitro; negative stain electron microscopy reveals an elongated architecture with hinge-like motion, consistent with the 2:4 stoichiometry (MTA:RBBP) seen in Drosophila NuRD.\",\n      \"method\": \"Recombinant expression in HEK293F cells; affinity purification; negative stain electron microscopy and 3D reconstruction\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural characterization by EM with biochemical reconstitution, single lab, limited functional validation\",\n      \"pmids\": [\"28179136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBBP7 functions as the DCAF substrate receptor in the CRL4B (DDB1-CUL4B-ROC1) E3 ubiquitin ligase complex, bridging the complex to HUWE1 and mediating its polyubiquitination and proteasomal degradation; RBBP7 depletion stabilizes HUWE1 and accelerates degradation of MCL-1 and BRCA1 (HUWE1 substrates).\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay in vitro and in cells; RBBP7 overexpression and depletion with Western blot for HUWE1, MCL-1, and BRCA1 levels\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus gain/loss of function ubiquitination assays with substrate-level readout, single lab\",\n      \"pmids\": [\"29738775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Double knockdown of Rbbp4 and Rbbp7 (but not individual knockdowns) causes embryonic lethality at the morula-to-blastocyst transition in mice, with cell cycle block, disrupted lineage specification, and a dramatic increase in H3.3 and H3K27ac abundance; ChIP-seq reveals H3.3 enrichment at promoters of RBBP4/7 target genes, indicating compensatory roles in H3.3 deposition and chromatin regulation.\",\n      \"method\": \"siRNA double knockdown in preimplantation embryos; ChIP-seq for H3.3 and H3K27ac; RNA-seq for gene expression; immunofluorescence for lineage markers\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with genome-wide ChIP-seq and RNA-seq, multiple orthogonal readouts establishing mechanistic role in H3.3 deposition\",\n      \"pmids\": [\"34709113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rbbp7 overexpression in hippocampal neurons reduces p300 levels, decreases tau acetylation at lysine 280, and reduces tau phosphorylation at AT8 and AT100 sites, thereby protecting against tau-induced neuronal death; in vitro Rbbp7 overexpression rescues TauP301L-induced cytotoxicity.\",\n      \"method\": \"Rbbp7 viral overexpression in PS19 mouse hippocampus; Western blot for p300, tau acetylation, and phosphorylation; neuronal survival quantification in CA1; cell viability assays in immortalized hippocampal cells and primary cortical neurons\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss/gain of function with multiple molecular readouts linking RBBP7 to p300 and tau modification, single lab\",\n      \"pmids\": [\"33978814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C. elegans RbAp46/48 (LIN-53) and HAT-1 are required for de novo CENP-A(HCP-3) and Mis18BP1(KNL-2) initial deposition at newly formed centromeres on artificial chromosomes; this requirement differs from centromere maintenance on endogenous chromosomes where KNL-2 acts upstream of LIN-53.\",\n      \"method\": \"RNAi depletion; microinjection of artificial chromosome constructs; immunofluorescence for CENP-A, KNL-2, and acetylation marks; epistasis analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic epistasis with multiple centromere assembly factors, de novo vs maintenance distinction established, ortholog study with mechanistic resolution\",\n      \"pmids\": [\"33872374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A hemizygous truncating mutation in RBBP7 (affecting the sixth WD40 domain) abrogates interaction with histone H4 and causes maturation arrest in spermatogenesis; Drosophila Caf1-55 (RBBP7 ortholog) knockdown in germ cells eliminates germ cells, while knockdown in cyst cells causes hyperproliferative testicular cells, and male infertility is rescued by wild-type human RBBP7 but not mutant variants.\",\n      \"method\": \"Human genetic variant identification; domain mapping by mutation analysis; Co-IP for histone H4 interaction; γH2AX and BRCA1 Western blot; Drosophila germline-specific and cyst cell-specific RNAi; rescue with wild-type vs. mutant human RBBP7\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic variant with domain-level functional mapping, cross-species rescue experiment with mutant vs. WT, multiple cellular readouts\",\n      \"pmids\": [\"37843278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SP1 transcription factor directly activates the RBBP7 promoter; RBBP7 in turn activates PI3K/AKT signaling to promote glycolysis (Warburg effect) and hepatocellular carcinoma cell proliferation.\",\n      \"method\": \"Dual-luciferase reporter assay for SP1-RBBP7 promoter; chromatin immunoprecipitation; Western blot for PI3K/AKT phosphorylation; CCK8 and colony formation; measurement of glycolytic enzymes and metabolites\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase directly confirm SP1-RBBP7 promoter interaction; PI3K/AKT activation established by phosphorylation assay; single lab\",\n      \"pmids\": [\"38368381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 functions as a novel E3 ubiquitin ligase via covalent engagement at Cys97; ynamide-containing small-molecule degraders covalently engage Cys97 of RBBP7 to recruit it as the E3 ligase responsible for targeted degradation of multiple proteins including CDK4, PDE5, PI3K, AKT, BRD4, and mutant EGFR.\",\n      \"method\": \"Chemical proteomics (activity-based protein profiling); proteome profiling after degrader treatment; covalent labeling with ynamide electrophile; functional validation of target degradation by Western blot; site-specific mutagenesis (Cys97)\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics with covalent site identification and functional degradation validation, single lab, novel mechanism\",\n      \"pmids\": [\"40600340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBBP7 directly deacetylates Acsl4 at lysine 401, reducing Acsl4 acetylation; deacetylation of Acsl4-K401 increases its enzyme activity by promoting ATP binding, thereby enhancing ferroptosis and promoting ovarian aging.\",\n      \"method\": \"Acetyl-proteomics; immunoprecipitation-mass spectrometry (IP-MS) identifying RBBP7 as direct Acsl4 deacetylation mediator; site-specific acetylation mutant analysis; Acsl4 enzyme activity assay; ferroptosis assays in vivo and in vitro\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification plus site-specific mutagenesis with enzyme activity readout; single lab; novel deacetylase substrate role\",\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) to erase repressive H3K9me3 marks, transcriptionally upregulating stemness gene expression and promoting breast cancer stem-like properties and metastasis.\",\n      \"method\": \"Co-immunoprecipitation for RBBP7-LSD1 interaction; ChIP-qPCR for H3K9me3 and LSD1 at stemness gene promoters; CRISPR/Cas9 deletion of RBBP7 super-enhancer; tumor sphere formation; tail vein metastasis model; PDO and PDX models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP-qPCR with in vivo validation and CRISPR genetic tools, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40038738\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBBP7 (RbAp46) is a WD40-repeat histone chaperone and chromatin adaptor that operates as a shared subunit of multiple chromatin-modifying complexes (NuRD, SIN3A, CoREST, CAF-1, CRL4); it facilitates histone deacetylation (as part of NuRD/HDAC complexes), mediates CENP-A deposition at centromeres as a substrate adaptor of CRL4 E3 ligase, directly deacetylates non-histone substrates (e.g., Acsl4-K401), targets HUWE1 for ubiquitin-proteasomal degradation via CRL4B, recruits LSD1 to erase repressive chromatin marks at stemness gene promoters, interacts with BRCA1-BRCT to modulate transcriptional activity, binds DNMT1 upon AMPK-mediated phosphorylation to inhibit DNA methylation, and is phosphorylated by AMPK to regulate nucleosome remodeling; its histone H4-binding function (via WD40 domains) is essential for spermatogenesis and proper chromosome segregation during meiosis and mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBBP7 (RbAp46) is a WD40-repeat histone chaperone and chromatin adaptor that serves as a shared subunit of histone-modifying machinery and links chromatin regulation to cell-cycle control, chromosome segregation, and gene expression [#11, #15]. Through its WD40 domains it binds histone H4, and this histone-binding function — abolished by a truncating mutation in the sixth WD40 domain — is essential for spermatogenesis, with male infertility rescued by wild-type but not mutant human RBBP7 [#20]. As part of histone deacetylase machinery it drives maturation-associated histone deacetylation required for chromosomal passenger complex localization and faithful meiotic chromosome segregation in oocytes [#11], while RBBP7 together with its paralog supports H3.3 deposition and chromatin regulation during preimplantation development [#17]. RBBP7 acts as the substrate-receptor (DCAF) subunit of CRL4 ubiquitin ligase complexes: as CRL4(RBBP7) it stabilizes soluble CENP-A and mediates its centromeric loading [#10], and as CRL4B it bridges and degrades HUWE1, thereby controlling MCL-1 and BRCA1 levels [#16]; orthologs are likewise required for CENP-A deposition at centromeres [#13, #19]. Beyond chromatin, RBBP7 is phosphorylated by AMPK, which enhances its interaction with DNMT1 to inhibit DNA methylation and remodel nucleosomes [#14], recruits LSD1 to erase repressive H3K9me3 at stemness gene promoters [#24], and directly deacetylates the non-histone substrate Acsl4 at K401 to modulate its enzyme activity and ferroptosis [#23]. RBBP7 also functions in transcriptional regulation through interactions with BRCA1-BRCT [#1] and HDAC1/Sp1 at target promoters [#9], and its expression-level changes modulate growth, apoptosis, and JNK signaling [#0, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established RBBP7 as a growth-regulatory gene downstream of a tumor suppressor, providing the first functional context for the protein.\",\n      \"evidence\": \"Suppression subtractive hybridization identifying RbAp46 as a WT1 target, with colony formation and growth assays\",\n      \"pmids\": [\"9765217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular mechanism of growth inhibition\", \"WT1-dependence shown but RBBP7 biochemical activity not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected RBBP7 to transcriptional regulation and DNA-damage signaling by mapping a WD-repeat-dependent interaction with the BRCA1 BRCT domain that represses p21 transactivation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, luciferase reporter and deletion mapping\",\n      \"pmids\": [\"11394910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence at endogenous BRCA1 targets genome-wide unknown\", \"Mechanism of disruption by DNA damage not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked RBBP7 overexpression to apoptotic and tumor-suppressive output via the JNK/GADD45 pathway, placing it upstream of a stress-signaling cascade.\",\n      \"evidence\": \"Inducible expression, JNK activity assays, dominant-negative JNK1 epistasis, xenografts (idx 2,3,4)\",\n      \"pmids\": [\"11433396\", \"14981905\", \"12767060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a chromatin adaptor activates JNK is not mechanistically defined\", \"Overexpression phenotypes may not reflect endogenous function\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Used the Drosophila ortholog p55 to place RBBP7 in pRB/E2F transcriptional repression, distinguishing cell-cycle-independent from proliferation-coupled repression modes.\",\n      \"evidence\": \"RNAi depletion of p55 with E2F target RT-PCR/reporter assays and RBF complex epistasis\",\n      \"pmids\": [\"15456884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mammalian validation not performed in this study\", \"Which complexes mediate each repression mode not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined RBBP7 as a substrate-specific adaptor (DCAF) of CRL4 required for centromeric loading and stabilization of CENP-A, giving it a defined enzymatic-complex role in centromere identity.\",\n      \"evidence\": \"Biochemical fractionation, quantitative imaging, RNAi of CUL4/DDB1/RBBP7 with CENP-A localization assays\",\n      \"pmids\": [\"25795299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination target relevant to CENP-A loading not identified\", \"Structural basis of CENP-A recognition unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that RBBP7-dependent histone deacetylation governs chromosomal passenger complex function and accurate chromosome segregation in oocytes, tying its chromatin role to meiotic fidelity.\",\n      \"evidence\": \"siRNA/morpholino knockdown in mouse oocytes with histone acetylation Western, CPC immunofluorescence, kinetochore-microtubule and SAC assays\",\n      \"pmids\": [\"24317350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HDAC complex mediates the relevant deacetylation not specified\", \"Direct CPC-RBBP7 link not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended RBBP7's chromatin-deacetylation role to reproductive tissue, showing it supports H4 acetylation-dependent cyclin D3 expression and decidualization under progesterone control.\",\n      \"evidence\": \"RNA knockdown in murine uterine stromal cells with H4 acetylation and cyclin D3 readouts and PR signaling demonstration\",\n      \"pmids\": [\"26040671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets at the cyclin D3 locus not mapped\", \"Complex context for the acetylation effect unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed RBBP7 in an HDAC1/Sp1 promoter-bound repressor complex controlling RECK and metastasis, connecting it to Ras-driven invasion.\",\n      \"evidence\": \"ChIP, DAPA, RECK reporter, shRNA knockdown and xenograft lung metastasis model\",\n      \"pmids\": [\"25885317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this complex is canonical NuRD/Sin3 not defined\", \"Direct vs. indirect Ras regulation of RBBP7 unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the centromere-loading function of RBBP7 orthologs can be independent of histone acetylation and known chromatin complexes, revealing a chaperone activity distinct from its HDAC-complex roles.\",\n      \"evidence\": \"RNAi and epistasis with CENP-A(HCP-3) and KNL-2 in C. elegans holocentromeres\",\n      \"pmids\": [\"26904949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of acetylation-independent CENP-A handoff unknown\", \"Direct mammalian confirmation of independence not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified AMPK as an upstream kinase that phosphorylates RBBP7 to enhance DNMT1 binding and inhibit DNA methylation, integrating metabolic signaling with chromatin/DNA-methylation control.\",\n      \"evidence\": \"Consensus-site identification, co-IP upon AMPK activation, pharmacological AMPK activation in HUVECs/mouse aorta and methylation assays\",\n      \"pmids\": [\"28143904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite mutagenesis validation not detailed\", \"Genome-wide methylation consequences not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural insight into RBBP7 within NuRD by reconstituting and imaging the MTA2-RBBP7 sub-complex, defining its stoichiometry and architecture.\",\n      \"evidence\": \"Recombinant expression, affinity purification and negative stain EM 3D reconstruction\",\n      \"pmids\": [\"28179136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution structure not obtained\", \"Functional consequence of the hinge motion untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a second CRL4-based role, with RBBP7 acting as the CRL4B DCAF that ubiquitinates HUWE1 and thereby controls MCL-1 and BRCA1 stability, expanding its E3-adaptor function to apoptosis and DNA-damage proteins.\",\n      \"evidence\": \"Co-IP, in vitro and cellular ubiquitination assays, gain/loss of function with HUWE1/MCL-1/BRCA1 Western blots\",\n      \"pmids\": [\"29738775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of HUWE1 recognition unknown\", \"Physiological contexts requiring this axis not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed paralog redundancy in development, with combined Rbbp4/Rbbp7 loss causing peri-implantation lethality and aberrant H3.3/H3K27ac, implicating RBBP7 in H3.3 deposition.\",\n      \"evidence\": \"siRNA double knockdown in mouse embryos with ChIP-seq, RNA-seq and lineage marker immunofluorescence\",\n      \"pmids\": [\"34709113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical role in H3.3 chaperoning not isolated from paralog\", \"Which complex mediates the embryonic function unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a neuroprotective role through RBBP7-mediated reduction of p300 and tau acetylation/phosphorylation, extending its regulation of acetylation machinery to neurodegeneration.\",\n      \"evidence\": \"Viral overexpression in PS19 hippocampus and TauP301L cells with Western blot and survival/viability assays\",\n      \"pmids\": [\"33978814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RBBP7 lowers p300 not defined\", \"Direct vs. indirect effect on tau modification unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished de novo from maintenance centromere assembly, showing RBBP7 ortholog and HAT-1 are needed for initial CENP-A deposition on artificial chromosomes versus a KNL-2-upstream maintenance pathway.\",\n      \"evidence\": \"RNAi, artificial chromosome microinjection and epistasis with CENP-A/KNL-2 in C. elegans\",\n      \"pmids\": [\"33872374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic role of acetylation (HAT-1) in initial deposition not fully resolved\", \"Mammalian de novo centromere relevance untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the WD40-H4 binding function of RBBP7 as essential for human spermatogenesis through a causative truncating mutation and cross-species rescue, providing a direct disease link.\",\n      \"evidence\": \"Human variant identification, domain mapping, H4 co-IP, and Drosophila germline/cyst-cell RNAi with WT-vs-mutant human RBBP7 rescue\",\n      \"pmids\": [\"37843278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream chromatin events in arresting spermatocytes not detailed\", \"Penetrance and broader phenotype spectrum not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RBBP7 to oncogenic metabolism, showing SP1 drives RBBP7 expression to activate PI3K/AKT and the Warburg effect in hepatocellular carcinoma.\",\n      \"evidence\": \"Luciferase, ChIP, PI3K/AKT phosphorylation Western, proliferation and glycolysis assays\",\n      \"pmids\": [\"38368381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking RBBP7 to PI3K/AKT not defined\", \"Direct vs. transcriptional effect unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered new catalytic and adaptor activities: a covalently druggable Cys97 conferring E3-ligase-like degradation of diverse targets, a direct deacetylase role toward Acsl4-K401, and LSD1 recruitment to demethylate stemness gene promoters.\",\n      \"evidence\": \"Chemical proteomics with Cys97 mutagenesis (idx 22); acetyl-proteomics/IP-MS with Acsl4 mutant and activity assays (idx 23); co-IP and ChIP-qPCR with CRISPR and in vivo models (idx 24)\",\n      \"pmids\": [\"40600340\", \"41478474\", \"40038738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous RBBP7 acts as a bona fide E3 ligase outside engineered degraders unclear\", \"Direct deacetylase catalytic mechanism for a WD40 protein not structurally resolved\", \"Specificity determinants for LSD1 recruitment unmapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBBP7's distinct activities — histone H4 chaperoning, HDAC-complex deacetylation, CRL4 substrate adaptation, AMPK-regulated DNMT1 binding, and the newly reported intrinsic deacetylase/E3 activities — are partitioned and regulated within a single WD40 protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model reconciling chaperone vs. catalytic claims\", \"Cell-type and complex context dictating which activity dominates not defined\", \"Endogenous (non-engineered) catalytic activities require independent confirmation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [11, 15, 20]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 16, 23]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 9, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [16, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 15, 17, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 11, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 16]}\n    ],\n    \"complexes\": [\"NuRD (MTA2-RBBP7)\", \"CRL4(RBBP7) / CRL4B E3 ubiquitin ligase\", \"HDAC1/Sp1 promoter complex\"],\n    \"partners\": [\"BRCA1\", \"HDAC1\", \"DNMT1\", \"HUWE1\", \"LSD1\", \"MTA2\", \"CENP-A\", \"histone H4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}