{"gene":"RUVBL1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1997,"finding":"RUVBL1 (TIP49) was identified as a TBP-interacting protein that forms a complex with TBP in nuclear extracts, isolated by affinity purification using histidine-tagged TBP. The protein contains Walker A and B motifs and shows structural similarity to bacterial RuvB, suggesting ATP-dependent enzymatic activity.","method":"Affinity purification (histidine-tagged TBP), immunoprecipitation, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP/affinity pulldown, single lab, two methods (affinity purification + IP)","pmids":["9196036"],"is_preprint":false},{"year":1998,"finding":"RUVBL1 (Pontin52) was identified as a nuclear protein that binds beta-catenin in the region of Armadillo repeats 2–5 and also binds TBP, forming an in vivo multiprotein complex with beta-catenin and LEF-1/TCF. This implicated RUVBL1 in the nuclear transcriptional function of beta-catenin.","method":"Yeast two-hybrid (identification), co-immunoprecipitation (in vivo complex validation), domain mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, domain mapping; independently replicated in multiple subsequent studies","pmids":["9843967"],"is_preprint":false},{"year":1998,"finding":"RUVBL1 was identified as a human protein homologous to RuvB; it co-immunoprecipitated with cellular proteins and was detected in the RNA polymerase II holoenzyme complex. Null mutation of the yeast homolog scRUVBL1 was nonviable, demonstrating it is essential for cell survival.","method":"Yeast two-hybrid (identification via RPA3 bait), co-immunoprecipitation, multi-step chromatographic purification, yeast null mutation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, purification, genetic viability assay); replicated across organisms","pmids":["9774387"],"is_preprint":false},{"year":1999,"finding":"RUVBL1 (TIP49a/TIP49) is an ATP-dependent DNA helicase with ssDNA-stimulated ATPase activity that unwinds DNA duplexes in the 3' to 5' direction, as established by in vitro enzyme assays with purified recombinant protein.","method":"In vitro ATPase assay, DNA helicase assay, UV cross-linking, recombinant protein purification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, multiple enzymatic assays; replicated by related studies","pmids":["10336418"],"is_preprint":false},{"year":1999,"finding":"RUVBL1 (TIP49a) and RUVBL2 (TIP49b) bind each other and are found together in the same ~700 kDa complex in cells. TIP49b has opposite DNA helicase polarity (5' to 3') compared to TIP49a (3' to 5'), and TIP49b does not complement the TIP49a yeast null mutation, indicating non-redundant functions.","method":"Co-immunoprecipitation, gel filtration (complex size), in vitro ATPase and helicase assays, yeast complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assays, Co-IP complex formation, genetic complementation; multiple orthogonal methods","pmids":["10428817"],"is_preprint":false},{"year":2000,"finding":"RUVBL1 (Pontin52) and RUVBL2 (Reptin52) interact with each other and both bind beta-catenin and TBP, but act antagonistically on beta-catenin/TCF transactivation in reporter gene assays. This antagonism is conserved in Drosophila (dpontin vs. dreptin in Wingless signaling).","method":"Reporter gene assay (transactivation), co-immunoprecipitation, Drosophila in vivo genetics","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional reporter assay, cross-species genetic validation; multiple orthogonal approaches","pmids":["11080158"],"is_preprint":false},{"year":2001,"finding":"RUVBL1 (TIP49a) functions as a plasminogen-binding protein on the U937 cell surface via a C-terminal lysine; it binds human plasminogen with a Kd of 0.57 μM and enhances plasminogen activation 8-fold, as demonstrated by ligand blotting and plasminogen activation assays.","method":"2D gel electrophoresis, ligand blotting with 125I-plasminogen, carboxypeptidase B sensitivity assay, kinetic binding assay, plasminogen activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab","pmids":["11027681"],"is_preprint":false},{"year":2002,"finding":"RUVBL1 (TIP49) modulates c-Myc-mediated apoptosis and also binds the E2F1 transactivation domain to modulate E2F1-dependent transforming and apoptotic activities, while the related factor TRRAP does not affect apoptosis. This distinguishes RUVBL1 as a specific cofactor for these transcription factors.","method":"Co-immunoprecipitation (E2F1 binding), functional apoptosis assays, dominant-negative mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding, functional assays with dominant-negative mutant, single lab","pmids":["12185582"],"is_preprint":false},{"year":2003,"finding":"RUVBL1 (TIP49) ATPase activity is required for beta-catenin-mediated neoplastic transformation and activation of TCF-dependent genes. An ATPase-deficient mutant (TIP49D302N) inhibited these activities. RUVBL1 was found in complexes with TIP60, TRRAP, and BAF53 chromatin-remodeling factors at the ITF-2 promoter, and its inhibition reduced histone acetylation near TCF-binding sites.","method":"ATPase-deficient mutant (D302N) expression, reporter gene assay, siRNA knockdown, chromatin immunoprecipitation (ChIP), co-immunoprecipitation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis, ChIP, Co-IP, siRNA, multiple orthogonal methods in one study","pmids":["14695187"],"is_preprint":false},{"year":2003,"finding":"RUVBL1 associates with alpha- and gamma-tubulin and localizes to the centrosome and mitotic spindle during mitosis, where its topology varies with mitotic stage. RUVBL1 promotes in vitro tubulin assembly.","method":"Protein affinity chromatography, co-immunoprecipitation, confocal immunofluorescence microscopy, GST pulldown, in vitro tubulin assembly assay","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pulldown, imaging, and functional assay; single lab","pmids":["14506706"],"is_preprint":false},{"year":2006,"finding":"The crystal structure of human RuvBL1 hexamer was solved at 2.2 Å resolution in complex with ADP. The structure revealed three domains: domains I and III mediate ATP binding/hydrolysis, while domain II (unique to eukaryotes, absent from bacterial RuvB) is a novel DNA/RNA-binding domain. RuvBL1 binds single-stranded DNA/RNA and double-stranded DNA, but shows only marginal ATPase activity in isolation, suggesting requirement for cofactors.","method":"X-ray crystallography (2.2 Å), DNA binding assays, ATPase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with biochemical validation, multiple assays","pmids":["17060327"],"is_preprint":false},{"year":2006,"finding":"Human TIP48 and TIP49 form a stable equimolar dodecameric complex (two stacked hexameric rings) with synergistic ATPase activity. Both proteins are required for ATPase activity (catalytic mutants in either abolish activity). No DNA helicase or branch migration activity was detected in the reconstituted complex.","method":"In vitro reconstitution, ATPase assay, ATPase-deficient mutants, negative stain electron microscopy (3D reconstruction at 20 Å)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution, mutagenesis, ATPase assay, and EM structure in one study","pmids":["17157868"],"is_preprint":false},{"year":2008,"finding":"Human RUVBL1 (Rvb1) is required for the histone acetyltransferase (HAT) activity of the Tip60/NuA4 complex but not for Ino80 or SRCAP complexes. RUVBL1 depletion increases persistence of phospho-H2AX after DNA damage, and this phenotype is phenocopied by Tip60 depletion. Histone H4 acetylation by Tip60 is required prior to dephosphorylation of phospho-H2AX.","method":"siRNA knockdown, in vitro HAT activity assay, immunofluorescence, H4 acetylation assay, epistasis between Rvb1 and Tip60/Ino80/SRCAP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro HAT activity assay, genetic epistasis, multiple knockdown comparisons, single lab with multiple orthogonal methods","pmids":["18285460"],"is_preprint":false},{"year":2008,"finding":"Yeast Rvb1 and Rvb2 form a heterohexameric ring with enhanced ATPase activity compared to individual proteins; ATPase is further stimulated by dsDNA with 5' or 3' overhangs. The complex exhibits ATP-dependent DNA helicase activity preferring 5' to 3' unwinding.","method":"In vitro reconstitution, ATPase assay, electron microscopy, DNA helicase assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, multiple enzymatic assays, EM structural analysis","pmids":["18234224"],"is_preprint":false},{"year":2008,"finding":"RUVBL1 depletion reduced RAD51 recruitment to chromatin and nuclear foci formation after DSBs and interstrand crosslinks by ~50%, without affecting DNA damage checkpoint signaling (H2AX phosphorylation). Histone deacetylase inhibitor treatment restored RAD51 foci, linking RUVBL1 to chromatin modification-dependent homologous recombination repair.","method":"siRNA knockdown, RAD51 foci immunofluorescence, chromatin fractionation, HDAC inhibitor rescue experiment","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined cellular phenotype, pharmacological rescue; single lab","pmids":["18834951"],"is_preprint":false},{"year":2009,"finding":"TIP48 and TIP49 play a major role in catalyzing H2A acetylation-induced H2A.Z exchange into nucleosomes via their ATPase activities. TIP60-mediated acetylation of nucleosomal H2A specifically facilitates the action of the complex containing TIP48/TIP49 in the H2A.Z exchange reaction.","method":"Purification of H2A.Z-interacting complexes, in vitro H2A.Z exchange assay, TIP60 HAT assay, ATPase-dependent mechanistic dissection","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted exchange assay, complex purification, enzymatic dissection; single lab with multiple orthogonal methods","pmids":["19696079"],"is_preprint":false},{"year":2010,"finding":"RUVBL1 and RUVBL2 associate with each PIKK family member (ATM, ATR, mTOR, DNA-PKcs, SMG-1, TRRAP), control PIKK mRNA and protein abundance upon knockdown, and promote the assembly of SMG-1-containing mRNA surveillance complexes in the cytoplasm during nonsense-mediated mRNA decay (NMD).","method":"Co-immunoprecipitation (RUVBL1/2 with PIKKs), siRNA knockdown (PIKK abundance and NMD), mRNP complex assembly assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP across multiple PIKKs, siRNA with functional NMD readout, multiple orthogonal methods","pmids":["20371770"],"is_preprint":false},{"year":2011,"finding":"RUVBL1 represses p53 transcription by binding to the p53 promoter, interfering with RNF20/hBRE1-mediated histone H2B monoubiquitination, and promoting PAF1-mediated histone H3K9 trimethylation. This mechanism underlies RUVBL1's ability to block p53-mediated apoptosis downstream of EHF transcription factor activation.","method":"ChIP, co-immunoprecipitation, siRNA knockdown, reporter assay, histone modification analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, siRNA, single lab with multiple methods","pmids":["21617703"],"is_preprint":false},{"year":2011,"finding":"The RuvBL1-RuvBL2 heterodimeric complex forms a dodecamer of two heterohexameric rings with alternating RUVBL1/RUVBL2 subunits bound to ADP/ATP. Truncation of domain II substantially increases ATPase activity, and domain II auto-inhibits helicase activity—showing that in vivo activities are regulated by cofactors via domain II conformational changes.","method":"X-ray crystallography (dodecamer with truncated DII), SAXS, ATPase assay, helicase assay","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, SAXS validation, multiple enzymatic assays in one study","pmids":["21933716"],"is_preprint":false},{"year":2011,"finding":"Hsp90 forms complexes with the RUVBL1/2 complex and the Tel2 complex, and Hsp90 inhibition reduces abundance of all PIKK family members and suppresses PIKK-mediated signaling, demonstrating that Hsp90 regulates PIKKs together with RUVBL1/2.","method":"Co-immunoprecipitation, Hsp90 inhibitor treatment, immunoblot for PIKK levels","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pharmacological inhibition, single lab","pmids":["21951644"],"is_preprint":false},{"year":2012,"finding":"Cryo-EM of the human RuvBL1-RuvBL2 complex revealed two coexisting conformations (compact and stretched) driven by movements in domain II (DII). DII domains connect the AAA+ core and expose DNA-binding regions, suggesting that these conformational transitions regulate the activity of RUVBL1-RUVBL2-containing complexes.","method":"Cryo-electron microscopy (~15 Å), image classification, nucleic acid binding analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural analysis with functional interpretation, single lab but rigorous structural method","pmids":["23002137"],"is_preprint":false},{"year":2012,"finding":"The TTT-RUVBL1/2 complex (TELO2-TTI1-TTI2 plus RUVBL1/2) is required for mTORC1 assembly into obligate dimers, its lysosomal localization, and its interaction with Rag GTPases. Energy depletion (loss of ATP from glucose/glutamine) disassembles and represses the TTT-RUVBL complex, thereby impairing mTORC1 function.","method":"Co-immunoprecipitation, siRNA knockdown, lysosome fractionation, AMPK/TSC epistasis analysis, metabolic flux assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, genetic epistasis, multiple orthogonal methods","pmids":["23142078"],"is_preprint":false},{"year":2013,"finding":"RuvbL1 and RuvbL2 function as disaggregases: they directly interact with aggregated substrate synphilin-1 near the opening of the central channel of the barrel structure, polypeptides with unfolded structures and amyloid fibrils stimulate RuvbL ATPase activity, and the complex promotes disassembly of protein aggregates and aggresome formation.","method":"siRNA screen, Co-IP (synphilin-1 interaction), ATPase stimulation assay (amyloid fibrils), aggregate disaggregation assay, yeast genetic studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ATPase assay with amyloid substrates, Co-IP, functional disaggregation assay, genetic analysis in yeast","pmids":["26303906"],"is_preprint":false},{"year":2014,"finding":"RuvBL1 and RuvBL2 co-purify with the Fanconi anemia (FA) core complex under native conditions, and depletion of RuvBL1-RuvBL2 leads to co-depletion of the FA core complex, causes DNA crosslinker sensitivity, chromosomal instability, and defective FA pathway activation. Conditional Ruvbl1 knockout in mouse hematopoietic cells causes aplastic anemia.","method":"Affinity purification-MS, co-immunoprecipitation, siRNA depletion, mouse conditional knockout, DNA crosslinker sensitivity assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — AP-MS, Co-IP, in vivo mouse KO with defined phenotype, multiple orthogonal methods","pmids":["25428364"],"is_preprint":false},{"year":2014,"finding":"YY1 oligomers preferentially interact with RUVBL1 (rather than RUVBL2) and DNA binding by YY1 oligomers is enhanced in the presence of RuvBL1-RuvBL2. YY1 and the ATPase activity of RUVBL2 are required for RAD51 foci formation during homologous recombination.","method":"Co-immunoprecipitation, electron microscopy, in vitro DNA binding assay, functional HR assay (RAD51 foci)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro binding assay, functional HR readout; single lab","pmids":["24990942"],"is_preprint":false},{"year":2014,"finding":"RUVBL1 localizes to the cytoplasm in pancreatic cancer cells where it directly binds filamentous actin (F-actin), increases G-actin concentration in cell protrusions, promotes peripheral actin polymerization, and thereby drives formation of membrane protrusions to enhance cancer cell invasion.","method":"siRNA knockdown, co-immunoprecipitation, confocal microscopy (F-actin colocalization), motility/invasion assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, localization by microscopy, functional invasion assay; single lab","pmids":["24728183"],"is_preprint":false},{"year":2015,"finding":"RUVBL1 localizes to structures of the mitotic spindle apparatus in anaphase-to-telophase transition, partially co-localizing with PLK1. PLK1 phosphorylates RUVBL1 (but not RUVBL2) in vitro, and they physically associate in vivo. siRNA knockdown of RuvBL proteins causes chromosome alignment and segregation defects, and the ATPase activity of RUVBL1 is indispensable for cell proliferation.","method":"Immunofluorescence microscopy, in vitro kinase assay (PLK1), co-immunoprecipitation, siRNA knockdown, ATPase-deficient mutant complementation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, Co-IP, live imaging, siRNA; single lab, multiple methods","pmids":["26201077"],"is_preprint":false},{"year":2015,"finding":"A domain within the INO80 ATPase subunit (Ino80INS) stimulates Rvb1/2 ATPase activity 16-fold and promotes dodecamerization. Cryo-EM and mass spectrometry show Ino80INS binds asymmetrically at the dodecamerization interface, creating a conformationally flexible dodecamer that collapses into hexamers upon ATP addition, demonstrating chaperone-like cycling behavior.","method":"ATPase assay, cryo-EM, crosslinking mass spectrometry, integrative structural modeling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with ATPase assay, cryo-EM structure, MS; multiple orthogonal methods in one study","pmids":["28591576"],"is_preprint":false},{"year":2017,"finding":"PRMT5 methylates RUVBL1 at arginine R205, which is required for TIP60-dependent mobilization of 53BP1 from DSBs and promotes homologous recombination. PRMT5-directed methylation of RUVBL1 is critically required for TIP60 acetyltransferase activity and histone H4K16 acetylation, which facilitates 53BP1 displacement. Methylation did not affect ATM activation.","method":"In vitro methyltransferase assay (PRMT5 on RUVBL1), mutant RUVBL1 (R205 site), TIP60 HAT activity assay, ChIP (H4K16Ac, 53BP1 foci), siRNA","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with specific mutant, ChIP, HAT activity assay; multiple orthogonal methods, rigorous controls","pmids":["28238654"],"is_preprint":false},{"year":2017,"finding":"The R2TP/Prefoldin-like complex interacts with the U5 snRNP, mediated primarily by the uncharacterized factor ZNHIT2. ZNHIT2 directly binds RUVBL2's DII domain; disruption of ZNHIT2 or RUVBL2 expression impacts U5 snRNP protein composition, implicating RUVBL1/2 in U5 snRNP assembly.","method":"Affinity purification-MS (multi-target), co-immunoprecipitation, siRNA knockdown with snRNP composition analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS, Co-IP, siRNA KD with complex composition readout; single lab","pmids":["28561026"],"is_preprint":false},{"year":2017,"finding":"Adenovirus E1A binds RUVBL1 via the C-terminus of E1A and is recruited to RUVBL1-regulated promoters in an interferon-dependent manner, suppressing interferon-stimulated gene transcriptional activation. Depletion of RUVBL1 impairs adenovirus growth but does not affect viral genome replication or S-phase induction.","method":"Co-immunoprecipitation (E1A-RUVBL1), ChIP, siRNA knockdown, viral growth assay, domain mapping","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ChIP at promoters, functional viral assay; single lab","pmids":["28122980"],"is_preprint":false},{"year":2018,"finding":"RUVBL1 interacts with DNAAF1 and IFT88 (ciliary intraflagellar transport protein). Loss of RUVBL1 perturbs DNAAF1/IFT88 co-localization, and RUVBL1 orthologs show asymmetric left-sided distribution at the embryonic node and zebrafish Kupffer's vesicle. Conditional Ruvbl1 deletion in tubular epithelial cells causes renal failure with fewer ciliated cells; deletion in motile-ciliated cells causes hydrocephalus. Cilia of Ruvbl1-negative cells lack crucial ciliary proteins, consistent with cytoplasmic pre-assembly of ciliary complexes.","method":"Co-immunoprecipitation (RUVBL1-DNAAF1-IFT88), conditional mouse knockout (renal epithelium, motile cilia), immunofluorescence, zebrafish asymmetry assay","journal":"Human molecular genetics / Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in two cell types with distinct phenotypes, Co-IP, live organism localization; multiple orthogonal methods","pmids":["29228333","29959317"],"is_preprint":false},{"year":2019,"finding":"The cryo-EM structure of the human R2TP co-chaperone complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) reveals that binding of PIH1D1 to the DII domain of RUVBL2 induces conformational rearrangements that destabilize an N-terminal segment of RUVBL2 acting as a gatekeeper to nucleotide exchange, thereby regulating RUVBL2 ATPase activity. This DII-mediated nucleotide access mechanism is proposed to be general.","method":"Cryo-EM structure determination, biochemical validation of conformational changes","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mechanistic biochemical validation, single lab","pmids":["31049401"],"is_preprint":false},{"year":2019,"finding":"CB-6644 is an allosteric small-molecule inhibitor of the RUVBL1/2 ATPase complex; drug-resistant clones carry mutations in RUVBL1 or RUVBL2, confirming on-target mechanism. Inhibition of RUVBL1/2 ATPase activity leads to cancer cell death and reduced tumor growth in AML and multiple myeloma xenograft models.","method":"In vitro ATPase inhibition assay, acquired resistance mutation mapping, xenograft tumor models","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic inhibition, resistance mutation validation (on-target), in vivo xenograft; multiple methods","pmids":["30640450"],"is_preprint":false},{"year":2019,"finding":"RUVBL1/2 ATPase activity is necessary for maturation/dissociation of the PAQosome (large RUVBL1/2-dependent multiprotein complex) and for DNA replication; its inhibition causes S-phase arrest and replication catastrophe in cancer cells.","method":"RUVBL1/2 ATPase inhibitor treatment, PAQosome complex analysis, S-phase flow cytometry, replication assay","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition, complex composition assay, cell cycle readout; single lab","pmids":["31883965"],"is_preprint":false},{"year":2019,"finding":"RUVBL1 promotes the RAF/MEK/ERK pathway by binding C-RAF and inhibiting phosphorylation of C-RAF at serine 259, thereby activating the pathway to promote lung cancer cell proliferation and invasion.","method":"Co-immunoprecipitation (RUVBL1-CRAF), immunoblot for pS259-CRAF, RUVBL1 knockout (cell proliferation/invasion assay), xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation analysis, KO functional assay; single lab","pmids":["29545175"],"is_preprint":false},{"year":2020,"finding":"RUVBL1-RUVBL2 complex controls assembly and composition of the gamma-tubulin ring complex (γTuRC) in human cells. RUVBL1/2 interacts with γTuRC subcomplexes but is absent from fully assembled γTuRC. Purified, RUVBL1/2-assembled recombinant γTuRC has microtubule nucleation activity and resembles native γTuRC by cryo-EM (~4.0 Å).","method":"siRNA knockdown (γTuRC assembly), heterologous coexpression reconstitution, cryo-EM structure (~4.0 Å), co-immunoprecipitation, microtubule nucleation assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of γTuRC assembly, cryo-EM structural validation, functional nucleation assay, KD in cells; multiple orthogonal methods","pmids":["33355144"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM reveals that DHX34, an RNA helicase regulating NMD initiation, directly interacts with RUVBL1-RUVBL2 in vitro and in cells. DHX34 binding induces extensive conformational changes in N-termini of every RUVBL2 subunit, stabilizing a conformation that cannot bind nucleotide, downregulating RUVBL2 ATP hydrolysis. ATPase-deficient mutants show DHX34 acts exclusively on RUVBL2 subunits.","method":"Cryo-EM structure, in vitro binding assay, co-immunoprecipitation, ATPase-deficient mutant analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural determination, in vitro biochemical validation, mutagenesis; multiple orthogonal methods","pmids":["33205750"],"is_preprint":false},{"year":2020,"finding":"Both excess and depletion of RUVBL1 impede DNA replication through transcription-dependent mechanisms. RUVBL1 overexpression increases c-Myc-dependent RNAPII pause release and transcription; RUVBL1 depletion increases Rpb1 ubiquitination and reduces RNAP II mobility, causing stalled RNAPII. Both states result in replication-transcription interference.","method":"siRNA knockdown, RUVBL1 overexpression, pSer2 CTD immunoblot, Rpb1 ubiquitination assay, FRAP, replication fork rate measurement","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary functional assays, single lab","pmids":["32846207"],"is_preprint":false},{"year":2021,"finding":"NOPCHAP1 (C12ORF45) acts as a PAQosome cofactor that bridges NOP58 to the PAQosome by making direct physical interactions with the CC-NOP domain of NOP58 and domain II of RUVBL1/2 AAA+ ATPases. NOPCHAP1 interaction with RUVBL1/2 is disrupted upon ATP binding, suggesting a nucleotide-regulated client-loading mechanism for C/D snoRNP biogenesis.","method":"Co-immunoprecipitation, in vitro direct binding assay, ATP competition assay, NOP58 KO cell analysis, proteomic pulldown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay, Co-IP, ATP-dependent release mechanism, domain-level specificity; multiple orthogonal methods","pmids":["33367824"],"is_preprint":false},{"year":2021,"finding":"RUVBL1 interacts with SMCHD1 and is present at D4Z4 chromatin; loss of RUVBL1 further derepresses DUX4 in FSHD myocytes, placing RUVBL1 in a SMCHD1-dependent chromatin repression pathway at the D4Z4 locus.","method":"Quantitative proteomics (SMCHD1 interactome), ChIP, siRNA knockdown, DUX4 derepression assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS interactome, ChIP, functional KD assay; single lab","pmids":["34880314"],"is_preprint":false},{"year":2022,"finding":"Rvb1/Rvb2 are enriched at promoters and mRNAs of alternative glucose metabolism genes during starvation. Engineered Rvb1/Rvb2 tethering to mRNAs is sufficient to sequester those mRNAs into mRNP granules, repress their translation, and drive further transcriptional upregulation of target genes, demonstrating coupling of transcription, mRNA localization, and translation.","method":"ChIP, RNA immunoprecipitation, mRNA tethering (engineered binding), stress granule imaging, ribosome profiling, genetic depletion","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered tethering experiment, ChIP, multiple readouts; single lab in yeast model","pmids":["36107469"],"is_preprint":false},{"year":2022,"finding":"LINC00839 (lncRNA) recruits RUVBL1 to the Tip60 complex and increases its acetyltransferase activity; the complex is guided to the NRF1 promoter and promotes H4K5 and H4K8 acetylation to upregulate NRF1 expression.","method":"Co-immunoprecipitation (LINC00839-RUVBL1-TIP60), ChIP (H4K5Ac, H4K8Ac at NRF1 promoter), siRNA/shRNA knockdown, reporter assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, functional rescue; single lab","pmids":["35876654"],"is_preprint":false},{"year":2022,"finding":"RUVBL1/2 inhibition significantly reduces histone H3K4me3 at the Nos2 and Il6 promoters and diminishes NF-κB recruitment to corresponding enhancers, demonstrating that RUVBL1/2 regulate macrophage pro-inflammatory gene expression through epigenetic H3K4 trimethylation.","method":"siRNA knockdown, RUVBL1/2 pharmacological inhibition, ChIP (H3K4me3, NF-κB), transcriptome analysis, functional NO production assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with histone modification readout, pharmacological inhibition, multiple gene targets; single lab","pmids":["34276666"],"is_preprint":false},{"year":2022,"finding":"DPCD directly interacts with RUVBL1 and RUVBL2 in vitro and in cells, predominantly via DII domains of RUVBL1/2. DPCD binding disrupts the dodecameric state of the RUVBL1/2 complex.","method":"Co-immunoprecipitation (in vivo), in vitro direct binding assay, SAXS, structural mass spectrometry, electron microscopy","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding, SAXS, EM structural analysis, Co-IP; multiple orthogonal methods, single lab","pmids":["35901867"],"is_preprint":false},{"year":2023,"finding":"GART methylates RUVBL1 at K7, enhancing RUVBL1 protein stability. This stabilization aberrantly activates the Wnt/β-catenin signaling pathway to induce tumor stemness in colorectal cancer.","method":"In vitro methyltransferase assay (GART on RUVBL1 K7), site-directed mutagenesis (E948 active site), co-immunoprecipitation, protein stability assay, β-catenin pathway reporter","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro methyltransferase assay, active site mutant, K7 site identification; single lab","pmids":["37439412"],"is_preprint":false},{"year":2023,"finding":"RUVBL1 controls MYC chromatin binding and modulates MYC-driven EEF1A1 expression and protein synthesis. A high-density CRISPR gene body scan identified the MYC-interacting residue(s) in RUVBL1 critical for this function.","method":"CRISPR screen (gene body scan), ChIP (MYC binding), RUVBL1 suppression (shRNA/CRISPR), protein synthesis assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR domain scan, ChIP, functional protein synthesis readout; single lab","pmids":["37075745"],"is_preprint":false},{"year":2024,"finding":"DTL ubiquitinates RUVBL1 and facilitates RUVBL1 binding to RUVBL2 and β-catenin. Ubiquitinated RUVBL1 promotes transcriptional regulation of NHEJ repair pathway genes via the RUVBL1/2–β-catenin complex, while attenuating TIP60-mediated H4K16 acetylation and HR repair, thereby enhancing radioresistance.","method":"Co-immunoprecipitation (DTL-RUVBL1, RUVBL1-RUVBL2-β-catenin), ubiquitination assay, ChIP (NHEJ gene promoters, H4K16Ac), siRNA/knockdown, in vitro and in vivo radioresistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay, Co-IP, ChIP; single lab, multiple methods","pmids":["38609375"],"is_preprint":false},{"year":2024,"finding":"RUVBL1 is required for MYC to establish oncogenic and immunoevasive gene expression in pancreatic ductal adenocarcinoma (PDAC). Degradation of RUVBL1 (auxin-degron system) arrests cancer but not untransformed cells and causes complete tumor regression in mice, preceded by immune cell infiltration.","method":"shRNA library screen (in vitro and in vivo), auxin-degron targeted degradation, gene expression analysis, in vivo PDAC mouse tumor model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic screen, targeted protein degradation, in vivo tumor regression; multiple orthogonal in vitro and in vivo methods","pmids":["38821858"],"is_preprint":false},{"year":2024,"finding":"RUVBL1 promotes enzalutamide resistance in prostate cancer by localizing to the cytoplasm upon enzalutamide treatment, enhancing recruitment of CRAF to plexin A1 (PLXNA1), and activating the downstream MAPK pathway.","method":"Co-immunoprecipitation (RUVBL1-CRAF-PLXNA1), subcellular fractionation (cytoplasmic RUVBL1), siRNA/CB-6644 inhibition, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, fractionation, pharmacological/genetic KD; single lab","pmids":["35508542"],"is_preprint":false},{"year":2024,"finding":"RUVBL1/2 reciprocally interact with YTHDF1 at 40S translation initiation complexes (identified by Co-IP and mass spectrometry). RUVBL1/2 loss stalls YTHDF1-driven oncogenic translation and nascent protein biosynthesis; ribosome sequencing shows impaired MAPK, RAS, and PI3K-AKT signaling translation upon RUVBL1/2 depletion.","method":"Co-immunoprecipitation, mass spectrometry, ribosome sequencing, siRNA knockdown, polysome profiling","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with MS, ribosome sequencing, multiple functional readouts; multiple orthogonal methods","pmids":["38900944"],"is_preprint":false}],"current_model":"RUVBL1 is an essential AAA+ ATPase that forms a heterohexameric (and dodecameric) ring complex with RUVBL2; its ATPase activity—regulated allosterically by domain II movements, client proteins (e.g., Ino80INS, DHX34, PIH1D1), and post-translational modifications including PLK1 phosphorylation (at mitosis), PRMT5-mediated R205 methylation (promoting TIP60 HAT activity and HR repair), GART-mediated K7 methylation (stabilizing the protein), and DTL-mediated ubiquitination (shifting it toward NHEJ)—underpins its roles as a scaffold and assembly chaperone for multiple nuclear complexes (TIP60/NuA4 HAT, INO80, SWR-C/SRCAP, R2TP co-chaperone, mTORC1-TTT, FA core complex, γTuRC, U5 snRNP, snoRNPs), where it facilitates H2A.Z exchange, histone acetylation, DNA damage repair (HR and NHEJ), beta-catenin/TCF transcription, PIKK assembly and NMD, cytoplasmic protein disaggregation, mitotic spindle function, and ciliogenesis."},"narrative":{"mechanistic_narrative":"RUVBL1 is an essential AAA+ ATPase that pairs with RUVBL2 to form heterohexameric and stacked dodecameric ring structures, serving as a scaffold and assembly chaperone for numerous nuclear and cytoplasmic multiprotein machines [PMID:10428817, PMID:17157868, PMID:9774387]. Each protomer comprises ATP-binding/hydrolysis domains (I and III) and a eukaryote-specific, nucleic-acid-binding domain II that auto-inhibits and allosterically gates ATPase and helicase activity through large conformational transitions [PMID:17060327, PMID:21933716, PMID:23002137]; client proteins and cofactors bind domain II to license catalysis and remodel oligomeric state, as shown for Ino80INS, the R2TP factors PIH1D1 and RPAP3, DHX34, NOPCHAP1, and DPCD [PMID:28591576, PMID:31049401, PMID:33205750, PMID:33367824, PMID:35901867]. Although isolated RUVBL1 was first characterized as an ssDNA-stimulated 3'-to-5' ATP-dependent DNA helicase, the assembled RUVBL1/2 complex shows only marginal intrinsic helicase activity and acts principally as an assembly chaperone whose ATPase cycle drives client loading and complex maturation [PMID:10336418, PMID:17157868, PMID:31883965]. Through this activity RUVBL1/2 builds and regulates chromatin-modifying and remodeling complexes—notably enabling TIP60/NuA4 histone acetyltransferase activity and ATPase-dependent H2A.Z exchange into nucleosomes [PMID:18285460, PMID:19696079]—and these functions underpin DNA double-strand break repair by both homologous recombination and non-homologous end joining, with PRMT5-mediated R205 methylation of RUVBL1 promoting TIP60 HAT activity, H4K16 acetylation and 53BP1 displacement to favor HR, and DTL-mediated ubiquitination shifting the balance toward NHEJ [PMID:28238654, PMID:18834951, PMID:38609375]. RUVBL1/2 is the assembly engine of broader R2TP/PAQosome chaperone activity required for PIKK stability and nonsense-mediated decay, mTORC1 dimerization and lysosomal localization, U5 snRNP and C/D snoRNP biogenesis, the Fanconi anemia core complex, and the γ-tubulin ring complex, and it supports mitotic spindle function and ciliogenesis [PMID:20371770, PMID:23142078, PMID:28561026, PMID:33367824, PMID:25428364, PMID:33355144, PMID:26201077, PMID:29228333, PMID:29959317]. In transcription it acts as a cofactor for the β-catenin/TCF, MYC and E2F1 programs and, with cytoplasmic disaggregase activity toward amyloid and aggregated substrates, links the complex to proteostasis [PMID:9843967, PMID:11080158, PMID:14695187, PMID:37075745, PMID:26303906]. RUVBL1/2 ATPase activity is required for cancer cell proliferation and is druggable by the allosteric inhibitor CB-6644, with MYC-driven tumors being acutely dependent on RUVBL1 [PMID:30640450, PMID:38821858].","teleology":[{"year":1998,"claim":"Established that RUVBL1 is a nuclear, RuvB-homologous protein physically linked to transcription machinery and essential for viability, framing it as a conserved enzyme with a core cellular role.","evidence":"Yeast two-hybrid and Co-IP placing it in the RNA Pol II holoenzyme, plus a lethal yeast null mutation; parallel work mapping its binding to β-catenin and TBP","pmids":["9774387","9843967","9196036"],"confidence":"High","gaps":["Did not define the biochemical activity of the protein","Did not identify the obligate RUVBL2 partner"]},{"year":1999,"claim":"Resolved the biochemical activity by showing recombinant RUVBL1 is an ATP-dependent 3'-to-5' DNA helicase and that it forms a ~700 kDa complex with the opposite-polarity, non-redundant RUVBL2.","evidence":"In vitro ATPase/helicase assays on purified protein, Co-IP, gel filtration, and yeast complementation","pmids":["10336418","10428817"],"confidence":"High","gaps":["Helicase activity later not detected in the reconstituted human complex","Physiological substrate of the helicase activity unknown"]},{"year":2000,"claim":"Showed RUVBL1 and RUVBL2 act antagonistically on β-catenin/TCF transactivation, establishing the paralog pair as functionally distinct regulators of Wnt-pathway transcription conserved to Drosophila.","evidence":"Reporter transactivation assays, Co-IP, and Drosophila genetics","pmids":["11080158"],"confidence":"High","gaps":["Mechanism of antagonism at chromatin not defined","Did not link to a specific chromatin-modifying complex"]},{"year":2003,"claim":"Connected RUVBL1 ATPase activity to chromatin-templated transcription, showing it operates within TIP60/TRRAP/BAF53 complexes to drive histone acetylation and β-catenin-mediated transformation.","evidence":"ATPase-dead D302N mutant, ChIP at the ITF-2 promoter, siRNA, and Co-IP; plus centrosome/spindle association and tubulin assembly assays","pmids":["14695187","14506706"],"confidence":"High","gaps":["Did not separate scaffolding from catalytic contributions to acetylation","Mitotic role only correlative at this stage"]},{"year":2008,"claim":"Defined a complex-specific requirement: RUVBL1 is needed for TIP60/NuA4 HAT activity (not INO80 or SRCAP) and links chromatin acetylation to DNA damage resolution, while the yeast Rvb1/Rvb2 hexamer was shown to be an enhanced ATPase/helicase.","evidence":"siRNA with in vitro HAT assays, epistasis between Rvb1/Tip60/Ino80/SRCAP, phospho-H2AX persistence, and RAD51 foci with HDAC-inhibitor rescue; in vitro reconstitution of yeast heterohexamer","pmids":["18285460","18834951","18234224"],"confidence":"High","gaps":["Mechanism coupling acetylation to phospho-H2AX dephosphorylation incomplete","Direct enzymatic role in HR not isolated from chromatin remodeling"]},{"year":2009,"claim":"Demonstrated the catalytic mechanism by which the TIP48/TIP49 ATPases drive TIP60-acetylation-dependent H2A.Z deposition into nucleosomes, defining a histone-exchange function.","evidence":"Purification of H2A.Z-interacting complexes with in vitro exchange and TIP60 HAT assays and ATPase-dependent dissection","pmids":["19696079"],"confidence":"High","gaps":["Structural basis of nucleosome engagement not resolved","In vivo locus-specificity of exchange not addressed"]},{"year":2011,"claim":"Established the structural logic of regulation: dodecameric assembly with domain II auto-inhibiting helicase activity, indicating in vivo function is gated by cofactors acting on DII.","evidence":"Crystallography of dodecamer with truncated DII, SAXS, and ATPase/helicase assays; earlier 2.2 Å hexamer structure defining DII as the nucleic-acid-binding domain","pmids":["21933716","17060327","17157868"],"confidence":"High","gaps":["Identity of physiological DII-acting cofactors not yet defined","Link between conformational state and specific complex assembly unclear"]},{"year":2012,"claim":"Established RUVBL1/2 as the core of the R2TP-related TTT chaperone that assembles PIKKs and mTORC1, coupling complex assembly to nutrient/energy status, and visualized the DII-driven conformational equilibrium.","evidence":"Co-IP across PIKK family members with NMD readout, TTT-mTORC1 fractionation/epistasis and metabolic flux assays, Hsp90 inhibition, and cryo-EM of compact/stretched states","pmids":["20371770","23142078","21951644","23002137"],"confidence":"High","gaps":["Stoichiometry of client handoff to mature complexes unresolved","How energy status mechanically disassembles the complex not defined"]},{"year":2014,"claim":"Broadened the assembly-chaperone role to the Fanconi anemia core complex and DNA crosslink repair, with in vivo knockout phenotypes, and implicated YY1 and cytoplasmic actin in additional functions.","evidence":"AP-MS/Co-IP with FA core, siRNA co-depletion, mouse conditional Ruvbl1 knockout causing aplastic anemia, plus YY1 EM/HR assays and F-actin binding/invasion assays","pmids":["25428364","24990942","24728183"],"confidence":"High","gaps":["Whether RUVBL1/2 directly chaperones FA assembly versus stabilizes it not fully separated","Cytoplasmic actin and YY1 roles rest on single-lab evidence"]},{"year":2017,"claim":"Identified post-translational control of RUVBL1 in DNA repair, with PRMT5-mediated R205 methylation enabling TIP60 HAT activity and HR, and resolved client-driven dodecamerization mechanistically via Ino80INS.","evidence":"In vitro methyltransferase assay with R205 mutant, HAT/ChIP assays for H4K16Ac and 53BP1; cryo-EM/XL-MS of Ino80INS-stimulated Rvb1/2; AP-MS linking R2TP to U5 snRNP via ZNHIT2","pmids":["28238654","28591576","28561026","28122980"],"confidence":"High","gaps":["Enzymes reversing R205 methylation unknown","How DII-binding clients select among many complexes not defined"]},{"year":2019,"claim":"Defined the general DII-gated nucleotide-exchange mechanism and validated RUVBL1/2 ATPase as a druggable, essential activity for tumor growth and DNA replication.","evidence":"Cryo-EM of R2TP (RPAP3-PIH1D1) showing DII-induced gatekeeper destabilization; CB-6644 allosteric inhibition with on-target resistance mutations and xenograft regression; PAQosome maturation and replication-catastrophe assays; C-RAF S259 pathway work","pmids":["31049401","30640450","31883965","29545175"],"confidence":"High","gaps":["How a single allosteric mechanism selectively affects diverse client complexes unresolved","Replication phenotype mixes direct and transcription-coupled effects"]},{"year":2020,"claim":"Extended the assembly-chaperone paradigm to γTuRC assembly, ciliary complex pre-assembly, and disaggregase activity, and resolved how the NMD helicase DHX34 down-tunes RUVBL2 ATPase via N-terminal conformational change.","evidence":"γTuRC reconstitution with cryo-EM and nucleation assays; conditional Ruvbl1 knockouts causing renal failure and hydrocephalus with cilia defects; cryo-EM of DHX34-RUVBL1/2; disaggregation/ATPase-stimulation assays with amyloid substrates; transcription-replication interference analysis","pmids":["33355144","29228333","29959317","33205750","26303906","32846207"],"confidence":"High","gaps":["How one ATPase serves cytoplasmic disaggregation and nuclear assembly is unclear","Selectivity for individual ciliary/spindle clients not defined"]},{"year":2024,"claim":"Established RUVBL1 as a MYC-cooperating dependency required for oncogenic and immunoevasive gene programs and oncogenic translation, and added further PTM control (GART K7 methylation, DTL ubiquitination) tuning Wnt signaling and repair-pathway choice.","evidence":"Auxin-degron and shRNA screens with in vivo PDAC regression, CRISPR gene-body MYC-interaction mapping with ChIP, YTHDF1/40S Co-IP-MS with ribosome sequencing; in vitro K7-methyltransferase and DTL-ubiquitination assays with ChIP and pathway readouts","pmids":["38821858","37075745","38900944","37439412","38609375","35876654","34276666","34880314","35508542","36107469"],"confidence":"High","gaps":["Whether MYC dependency reflects direct chromatin scaffolding versus chaperone-mediated complex assembly is unresolved","Several PTM/cancer findings rest on single-lab evidence"]},{"year":null,"claim":"How a single RUVBL1/2 ATPase cycle and DII-gated conformational switch achieve selective, ordered assembly of dozens of distinct nuclear and cytoplasmic client complexes remains the central open mechanistic question.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking client identity at DII to a defined ATPase output","Rules governing partition between disaggregation, histone exchange, and chaperone roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,4,11,13,18,26,33,34]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,4,11,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,10,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[22,27]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[27,36]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,22,25,49]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9,36]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9,25]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,12,15,28,42,43]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14,23,28,47]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,8,17,46]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,21,29,39,22]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[16,29,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,21,35,49]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[26,34,36]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[34,38]}],"complexes":["R2TP/PAQosome (RUVBL1-RUVBL2-RPAP3-PIH1D1)","TIP60/NuA4 HAT complex","TTT-RUVBL1/2 (mTORC1 assembly)","Fanconi anemia core complex"],"partners":["RUVBL2","TIP60","PIH1D1","DHX34","CTNNB1","TBP","NOPCHAP1","DPCD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y265","full_name":"RuvB-like 1","aliases":["49 kDa TATA box-binding protein-interacting protein","49 kDa TBP-interacting protein","54 kDa erythrocyte cytosolic protein","ECP-54","INO80 complex subunit H","Nuclear matrix protein 238","NMP 238","Pontin 52","TIP49a","TIP60-associated protein 54-alpha","TAP54-alpha"],"length_aa":456,"mass_kda":50.2,"function":"Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity (PubMed:17157868, PubMed:33205750). Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:14966270). The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:14966270). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding (PubMed:16230350, PubMed:21303910). Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex (PubMed:10882073, PubMed:16014379). Essential for cell proliferation (PubMed:14506706). May be able to bind plasminogen at cell surface and enhance plasminogen activation (PubMed:11027681)","subcellular_location":"Nucleus matrix; Nucleus, nucleoplasm; Cytoplasm; Membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Dynein axonemal particle","url":"https://www.uniprot.org/uniprotkb/Q9Y265/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RUVBL1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000175792","cell_line_id":"CID001726","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"NOP58","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"PFDN6","stoichiometry":4.0},{"gene":"POLR2B","stoichiometry":4.0},{"gene":"PTGES3","stoichiometry":4.0},{"gene":"YY1","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"FKBP8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001726","total_profiled":1310},"omim":[{"mim_id":"620390","title":"HEAT REPEAT-CONTAINING PROTEIN 1; HEATR1","url":"https://www.omim.org/entry/620390"},{"mim_id":"611479","title":"GPN-LOOP GTPase 1; GPN1","url":"https://www.omim.org/entry/611479"},{"mim_id":"611477","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 3; RPAP3","url":"https://www.omim.org/entry/611477"},{"mim_id":"611476","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 2; RPAP2","url":"https://www.omim.org/entry/611476"},{"mim_id":"611475","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 1; RPAP1","url":"https://www.omim.org/entry/611475"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RUVBL1"},"hgnc":{"alias_symbol":["TIP49","NMP238","RVB1","TIP49a","Pontin52","ECP54","TIH1","Rvb1","INO80H"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y265","domains":[{"cath_id":"3.40.50.300","chopping":"42-91_297-361","consensus_level":"high","plddt":91.943,"start":42,"end":361},{"cath_id":"2.40.50.360","chopping":"125-234","consensus_level":"medium","plddt":85.6467,"start":125,"end":234},{"cath_id":"1.10.8.60","chopping":"367-447","consensus_level":"high","plddt":93.3033,"start":367,"end":447}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y265","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y265-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y265-F1-predicted_aligned_error_v6.png","plddt_mean":87.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RUVBL1","jax_strain_url":"https://www.jax.org/strain/search?query=RUVBL1"},"sequence":{"accession":"Q9Y265","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y265.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y265/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y265"}},"corpus_meta":[{"pmid":"11080158","id":"PMC_11080158","title":"Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11080158","citation_count":238,"is_preprint":false},{"pmid":"19524533","id":"PMC_19524533","title":"RVB1/RVB2: running rings around molecular biology.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19524533","citation_count":194,"is_preprint":false},{"pmid":"23142078","id":"PMC_23142078","title":"Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23142078","citation_count":186,"is_preprint":false},{"pmid":"9843967","id":"PMC_9843967","title":"Pontin52, an interaction partner of beta-catenin, binds to the TATA box binding protein.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9843967","citation_count":153,"is_preprint":false},{"pmid":"17060327","id":"PMC_17060327","title":"Crystal structure of the human AAA+ protein RuvBL1.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17060327","citation_count":137,"is_preprint":false},{"pmid":"20371770","id":"PMC_20371770","title":"AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay.","date":"2010","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20371770","citation_count":131,"is_preprint":false},{"pmid":"28238654","id":"PMC_28238654","title":"PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28238654","citation_count":131,"is_preprint":false},{"pmid":"18285460","id":"PMC_18285460","title":"Human Rvb1/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18285460","citation_count":130,"is_preprint":false},{"pmid":"10428817","id":"PMC_10428817","title":"TIP49b, a new RuvB-like DNA helicase, is included in a complex together with another RuvB-like DNA helicase, TIP49a.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10428817","citation_count":122,"is_preprint":false},{"pmid":"9774387","id":"PMC_9774387","title":"An eukaryotic RuvB-like protein (RUVBL1) essential for growth.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9774387","citation_count":117,"is_preprint":false},{"pmid":"31665067","id":"PMC_31665067","title":"CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to enhance the transcriptional activity of β-catenin/LEF1 complex via effects on chromatin remodeling.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31665067","citation_count":114,"is_preprint":false},{"pmid":"21933716","id":"PMC_21933716","title":"Structural and functional insights into a dodecameric molecular machine - the RuvBL1/RuvBL2 complex.","date":"2011","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/21933716","citation_count":105,"is_preprint":false},{"pmid":"9196036","id":"PMC_9196036","title":"Molecular cloning of a rat 49-kDa TBP-interacting protein (TIP49) that is highly homologous to the bacterial RuvB.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9196036","citation_count":100,"is_preprint":false},{"pmid":"28561026","id":"PMC_28561026","title":"R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28561026","citation_count":96,"is_preprint":false},{"pmid":"14695187","id":"PMC_14695187","title":"TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/14695187","citation_count":90,"is_preprint":false},{"pmid":"16087886","id":"PMC_16087886","title":"Myc interacts genetically with Tip48/Reptin and Tip49/Pontin to control growth and proliferation during Drosophila development.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16087886","citation_count":86,"is_preprint":false},{"pmid":"17157868","id":"PMC_17157868","title":"Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17157868","citation_count":85,"is_preprint":false},{"pmid":"24023044","id":"PMC_24023044","title":"Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement.","date":"2014","source":"Arthritis care & research","url":"https://pubmed.ncbi.nlm.nih.gov/24023044","citation_count":85,"is_preprint":false},{"pmid":"23530256","id":"PMC_23530256","title":"Chaperone-like activity of the AAA+ proteins Rvb1 and Rvb2 in the assembly of various complexes.","date":"2013","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23530256","citation_count":83,"is_preprint":false},{"pmid":"18234224","id":"PMC_18234224","title":"Yeast Rvb1 and Rvb2 are ATP-dependent DNA helicases that form a heterohexameric complex.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18234224","citation_count":77,"is_preprint":false},{"pmid":"10336418","id":"PMC_10336418","title":"A rat RuvB-like protein, TIP49a, is a germ cell-enriched novel DNA helicase.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10336418","citation_count":72,"is_preprint":false},{"pmid":"12185582","id":"PMC_12185582","title":"TIP49, but not TRRAP, modulates c-Myc and E2F1 dependent apoptosis.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12185582","citation_count":72,"is_preprint":false},{"pmid":"30640450","id":"PMC_30640450","title":"CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity.","date":"2019","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30640450","citation_count":70,"is_preprint":false},{"pmid":"33129013","id":"PMC_33129013","title":"RUVBL1-RUVBL2 AAA-ATPase: a versatile scaffold for multiple complexes and functions.","date":"2020","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33129013","citation_count":63,"is_preprint":false},{"pmid":"20130677","id":"PMC_20130677","title":"Rvb1-Rvb2: essential ATP-dependent helicases for critical complexes.","date":"2010","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/20130677","citation_count":60,"is_preprint":false},{"pmid":"31883965","id":"PMC_31883965","title":"RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.","date":"2019","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31883965","citation_count":60,"is_preprint":false},{"pmid":"14506706","id":"PMC_14506706","title":"The ATP-dependent helicase RUVBL1/TIP49a associates with tubulin during mitosis.","date":"2003","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/14506706","citation_count":60,"is_preprint":false},{"pmid":"11027681","id":"PMC_11027681","title":"Purification, cloning, and characterization of a profibrinolytic plasminogen-binding protein, TIP49a.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11027681","citation_count":57,"is_preprint":false},{"pmid":"19696079","id":"PMC_19696079","title":"Cooperative action of TIP48 and TIP49 in H2A.Z exchange catalyzed by acetylation of nucleosomal H2A.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19696079","citation_count":54,"is_preprint":false},{"pmid":"23002137","id":"PMC_23002137","title":"Conformational transitions regulate the exposure of a DNA-binding domain in the RuvBL1-RuvBL2 complex.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23002137","citation_count":51,"is_preprint":false},{"pmid":"29294089","id":"PMC_29294089","title":"Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis.","date":"2018","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29294089","citation_count":49,"is_preprint":false},{"pmid":"26303906","id":"PMC_26303906","title":"RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26303906","citation_count":47,"is_preprint":false},{"pmid":"33355144","id":"PMC_33355144","title":"Assembly of the asymmetric human γ-tubulin ring complex by RUVBL1-RUVBL2 AAA ATPase.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33355144","citation_count":47,"is_preprint":false},{"pmid":"35876654","id":"PMC_35876654","title":"LINC00839 promotes colorectal cancer progression by recruiting RUVBL1/Tip60 complexes to activate NRF1.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35876654","citation_count":44,"is_preprint":false},{"pmid":"28591576","id":"PMC_28591576","title":"Regulation of Rvb1/Rvb2 by a Domain within the INO80 Chromatin Remodeling Complex Implicates the Yeast Rvbs as Protein Assembly Chaperones.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28591576","citation_count":44,"is_preprint":false},{"pmid":"24990942","id":"PMC_24990942","title":"Structure of Yin Yang 1 oligomers that cooperate with RuvBL1-RuvBL2 ATPases.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24990942","citation_count":43,"is_preprint":false},{"pmid":"9588198","id":"PMC_9588198","title":"TIP49, homologous to the bacterial DNA helicase RuvB, acts as an autoantigen in human.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9588198","citation_count":42,"is_preprint":false},{"pmid":"31049401","id":"PMC_31049401","title":"Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM.","date":"2019","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/31049401","citation_count":42,"is_preprint":false},{"pmid":"20412048","id":"PMC_20412048","title":"Oligomeric assembly and interactions within the human RuvB-like RuvBL1 and RuvBL2 complexes.","date":"2010","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/20412048","citation_count":39,"is_preprint":false},{"pmid":"20130681","id":"PMC_20130681","title":"Comparison of the multiple oligomeric structures observed for the Rvb1 and Rvb2 proteins.","date":"2010","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/20130681","citation_count":38,"is_preprint":false},{"pmid":"21951644","id":"PMC_21951644","title":"Heat shock protein 90 regulates phosphatidylinositol 3-kinase-related protein kinase family proteins together with the RUVBL1/2 and Tel2-containing co-factor complex.","date":"2011","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/21951644","citation_count":38,"is_preprint":false},{"pmid":"18834951","id":"PMC_18834951","title":"RAD51 foci formation in response to DNA damage is modulated by TIP49.","date":"2008","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18834951","citation_count":37,"is_preprint":false},{"pmid":"25428364","id":"PMC_25428364","title":"Abundance of the Fanconi anaemia core complex is regulated by the RuvBL1 and RuvBL2 AAA+ ATPases.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25428364","citation_count":36,"is_preprint":false},{"pmid":"21617703","id":"PMC_21617703","title":"A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21617703","citation_count":36,"is_preprint":false},{"pmid":"22540023","id":"PMC_22540023","title":"Integrated regulation of PIKK-mediated stress responses by AAA+ proteins RUVBL1 and RUVBL2.","date":"2012","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22540023","citation_count":35,"is_preprint":false},{"pmid":"29228333","id":"PMC_29228333","title":"DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29228333","citation_count":30,"is_preprint":false},{"pmid":"22748767","id":"PMC_22748767","title":"Large-scale conformational flexibility determines the properties of AAA+ TIP49 ATPases.","date":"2012","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/22748767","citation_count":29,"is_preprint":false},{"pmid":"26201077","id":"PMC_26201077","title":"Chromosome Missegregation Associated with RUVBL1 Deficiency.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26201077","citation_count":28,"is_preprint":false},{"pmid":"37439412","id":"PMC_37439412","title":"GART Functions as a Novel Methyltransferase in the RUVBL1/β-Catenin Signaling Pathway to Promote Tumor Stemness in Colorectal Cancer.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37439412","citation_count":27,"is_preprint":false},{"pmid":"14675489","id":"PMC_14675489","title":"Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a.","date":"2003","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14675489","citation_count":26,"is_preprint":false},{"pmid":"35508542","id":"PMC_35508542","title":"RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35508542","citation_count":25,"is_preprint":false},{"pmid":"37075745","id":"PMC_37075745","title":"Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1-EEF1A1 Axis.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37075745","citation_count":25,"is_preprint":false},{"pmid":"10524211","id":"PMC_10524211","title":"Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10524211","citation_count":25,"is_preprint":false},{"pmid":"32789167","id":"PMC_32789167","title":"Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32789167","citation_count":25,"is_preprint":false},{"pmid":"26711270","id":"PMC_26711270","title":"A Novel Interaction of Ecdysoneless (ECD) Protein with R2TP Complex Component RUVBL1 Is Required for the Functional Role of ECD in Cell Cycle Progression.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26711270","citation_count":25,"is_preprint":false},{"pmid":"24728183","id":"PMC_24728183","title":"RUVBL1 directly binds actin filaments and induces formation of cell protrusions to promote pancreatic cancer cell invasion.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24728183","citation_count":23,"is_preprint":false},{"pmid":"29959317","id":"PMC_29959317","title":"Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29959317","citation_count":23,"is_preprint":false},{"pmid":"31018511","id":"PMC_31018511","title":"Identification of RUVBL1 and RUVBL2 as Novel Cellular Interactors of the Ebola Virus Nucleoprotein.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31018511","citation_count":22,"is_preprint":false},{"pmid":"10565543","id":"PMC_10565543","title":"A notable example of an evolutionary conserved gene: studies on a putative DNA helicase TIP49.","date":"1999","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/10565543","citation_count":21,"is_preprint":false},{"pmid":"28919439","id":"PMC_28919439","title":"Pih1p-Tah1p Puts a Lid on Hexameric AAA+ ATPases Rvb1/2p.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28919439","citation_count":21,"is_preprint":false},{"pmid":"30834599","id":"PMC_30834599","title":"The plant Pontin and Reptin homologues, RuvBL1 and RuvBL2a, colocalize with TERT and TRB proteins in vivo, and participate in telomerase biogenesis.","date":"2019","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30834599","citation_count":21,"is_preprint":false},{"pmid":"27722820","id":"PMC_27722820","title":"Downregulation of RUVBL1 inhibits proliferation of lung adenocarcinoma cells by G1/S phase cell cycle arrest via multiple mechanisms.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27722820","citation_count":21,"is_preprint":false},{"pmid":"36438486","id":"PMC_36438486","title":"Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/36438486","citation_count":20,"is_preprint":false},{"pmid":"28341484","id":"PMC_28341484","title":"RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer.","date":"2017","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/28341484","citation_count":20,"is_preprint":false},{"pmid":"33367824","id":"PMC_33367824","title":"NOPCHAP1 is a PAQosome cofactor that helps loading NOP58 on RUVBL1/2 during box C/D snoRNP biogenesis.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33367824","citation_count":20,"is_preprint":false},{"pmid":"25636407","id":"PMC_25636407","title":"Yeast rvb1 and rvb2 proteins oligomerize as a conformationally variable dodecamer with low frequency.","date":"2015","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25636407","citation_count":18,"is_preprint":false},{"pmid":"31721195","id":"PMC_31721195","title":"Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31721195","citation_count":18,"is_preprint":false},{"pmid":"38609375","id":"PMC_38609375","title":"RUVBL1 ubiquitination by DTL promotes RUVBL1/2-β-catenin-mediated transcriptional regulation of NHEJ pathway and enhances radiation resistance in breast cancer.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38609375","citation_count":17,"is_preprint":false},{"pmid":"29545175","id":"PMC_29545175","title":"RUVBL1, a novel C-RAF-binding protein, activates the RAF/MEK/ERK pathway to promote lung cancer tumorigenesis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29545175","citation_count":17,"is_preprint":false},{"pmid":"28122980","id":"PMC_28122980","title":"Suppression of Type I Interferon Signaling by E1A via RuvBL1/Pontin.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28122980","citation_count":16,"is_preprint":false},{"pmid":"38821858","id":"PMC_38821858","title":"Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.","date":"2024","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/38821858","citation_count":15,"is_preprint":false},{"pmid":"38900944","id":"PMC_38900944","title":"RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis.","date":"2024","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38900944","citation_count":14,"is_preprint":false},{"pmid":"33205750","id":"PMC_33205750","title":"Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33205750","citation_count":14,"is_preprint":false},{"pmid":"28028178","id":"PMC_28028178","title":"C-FLIPL Modulated Wnt/β-Catenin Activation via Association with TIP49 Protein.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28028178","citation_count":13,"is_preprint":false},{"pmid":"32745900","id":"PMC_32745900","title":"RUVBL1 is an amplified epigenetic factor promoting proliferation and inhibiting differentiation program in head and neck squamous cancers.","date":"2020","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32745900","citation_count":13,"is_preprint":false},{"pmid":"30062057","id":"PMC_30062057","title":"Pontin/Tip49 negatively regulates JNK-mediated cell death in Drosophila.","date":"2018","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30062057","citation_count":13,"is_preprint":false},{"pmid":"10842076","id":"PMC_10842076","title":"Expression of Xenopus homologs of the beta-catenin binding protein pontin52.","date":"2000","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/10842076","citation_count":13,"is_preprint":false},{"pmid":"34276666","id":"PMC_34276666","title":"RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34276666","citation_count":13,"is_preprint":false},{"pmid":"37541187","id":"PMC_37541187","title":"Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression.","date":"2023","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37541187","citation_count":13,"is_preprint":false},{"pmid":"39665272","id":"PMC_39665272","title":"The Lyn/RUVBL1 Complex Promotes Colorectal Cancer Liver Metastasis by Regulating Arachidonic Acid Metabolism Through Chromatin Remodeling.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39665272","citation_count":12,"is_preprint":false},{"pmid":"35493294","id":"PMC_35493294","title":"Involvement of RUVBL1 in WNT/β-Catenin Signaling in Oral Squamous Cell Carcinoma.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35493294","citation_count":12,"is_preprint":false},{"pmid":"35364523","id":"PMC_35364523","title":"Discovery of small-molecule inhibitors of RUVBL1/2 ATPase.","date":"2022","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35364523","citation_count":12,"is_preprint":false},{"pmid":"26831523","id":"PMC_26831523","title":"Proteomic and Genomic Analyses of the Rvb1 and Rvb2 Interaction Network upon Deletion of R2TP Complex Components.","date":"2016","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/26831523","citation_count":11,"is_preprint":false},{"pmid":"37076452","id":"PMC_37076452","title":"RUVBL1-modulated chromatin remodeling alters the transcriptional activity of oncogenic CTNNB1 in uveal melanoma.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37076452","citation_count":9,"is_preprint":false},{"pmid":"27066592","id":"PMC_27066592","title":"The Relationship between RUVBL1 (Pontin, TIP49, NMP238) and BCL6 in Benign and Malignant Human Lymphoid Tissues.","date":"2016","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/27066592","citation_count":8,"is_preprint":false},{"pmid":"36592991","id":"PMC_36592991","title":"EIF3D promotes resistance to 5-fluorouracil in colorectal cancer through upregulating RUVBL1.","date":"2023","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/36592991","citation_count":8,"is_preprint":false},{"pmid":"34164343","id":"PMC_34164343","title":"RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34164343","citation_count":8,"is_preprint":false},{"pmid":"32846207","id":"PMC_32846207","title":"Deregulated levels of RUVBL1 induce transcription-dependent replication stress.","date":"2020","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32846207","citation_count":7,"is_preprint":false},{"pmid":"35901867","id":"PMC_35901867","title":"Deciphering cellular and molecular determinants of human DPCD protein in complex with RUVBL1/RUVBL2 AAA-ATPases.","date":"2022","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35901867","citation_count":7,"is_preprint":false},{"pmid":"17302941","id":"PMC_17302941","title":"Functional and comparative characterization of Saccharomyces cerevisiae RVB1 and RVB2 genes with bacterial Ruv homologues.","date":"2007","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/17302941","citation_count":7,"is_preprint":false},{"pmid":"37349884","id":"PMC_37349884","title":"Downregulation of AHNAK2 inhibits cell cycle of lung adenocarcinoma cells by interacting with RUVBL1.","date":"2023","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37349884","citation_count":7,"is_preprint":false},{"pmid":"18765919","id":"PMC_18765919","title":"Cloning, expression, purification, crystallization and preliminary X-ray analysis of the human RuvBL1-RuvBL2 complex.","date":"2008","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/18765919","citation_count":7,"is_preprint":false},{"pmid":"36107469","id":"PMC_36107469","title":"Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36107469","citation_count":6,"is_preprint":false},{"pmid":"28574207","id":"PMC_28574207","title":"Human DNA helicase, RuvBL1 and its Chlamydomonas homologue, CrRuvBL1 plays an important role in ciliogenesis.","date":"2017","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28574207","citation_count":6,"is_preprint":false},{"pmid":"38042247","id":"PMC_38042247","title":"IRX2 regulates endometrial carcinoma oncogenesis by transcriptional repressing RUVBL1.","date":"2023","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38042247","citation_count":5,"is_preprint":false},{"pmid":"10902922","id":"PMC_10902922","title":"Chromosome mapping and expression of human tip49 family genes.","date":"2000","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/10902922","citation_count":4,"is_preprint":false},{"pmid":"39201707","id":"PMC_39201707","title":"Molecular Signatures of CB-6644 Inhibition of the RUVBL1/2 Complex in Multiple Myeloma.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201707","citation_count":4,"is_preprint":false},{"pmid":"33775623","id":"PMC_33775623","title":"Leishmania major RUVBL1 has a hexameric conformation in solution and, in the presence of RUVBL2, forms a heterodimer with ATPase activity.","date":"2021","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33775623","citation_count":4,"is_preprint":false},{"pmid":"39670302","id":"PMC_39670302","title":"Regulation of the β‑catenin/LEF‑1 pathway by the siRNA knockdown of RUVBL1 expression inhibits breast cancer cell proliferation, migration and invasion.","date":"2024","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39670302","citation_count":4,"is_preprint":false},{"pmid":"34880314","id":"PMC_34880314","title":"A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34880314","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48186,"output_tokens":12539,"usd":0.166322,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23866,"output_tokens":5943,"usd":0.133953,"stage2_stop_reason":"end_turn"},"total_usd":0.300275,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"RUVBL1 (TIP49) was identified as a TBP-interacting protein that forms a complex with TBP in nuclear extracts, isolated by affinity purification using histidine-tagged TBP. The protein contains Walker A and B motifs and shows structural similarity to bacterial RuvB, suggesting ATP-dependent enzymatic activity.\",\n      \"method\": \"Affinity purification (histidine-tagged TBP), immunoprecipitation, sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP/affinity pulldown, single lab, two methods (affinity purification + IP)\",\n      \"pmids\": [\"9196036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RUVBL1 (Pontin52) was identified as a nuclear protein that binds beta-catenin in the region of Armadillo repeats 2–5 and also binds TBP, forming an in vivo multiprotein complex with beta-catenin and LEF-1/TCF. This implicated RUVBL1 in the nuclear transcriptional function of beta-catenin.\",\n      \"method\": \"Yeast two-hybrid (identification), co-immunoprecipitation (in vivo complex validation), domain mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, domain mapping; independently replicated in multiple subsequent studies\",\n      \"pmids\": [\"9843967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RUVBL1 was identified as a human protein homologous to RuvB; it co-immunoprecipitated with cellular proteins and was detected in the RNA polymerase II holoenzyme complex. Null mutation of the yeast homolog scRUVBL1 was nonviable, demonstrating it is essential for cell survival.\",\n      \"method\": \"Yeast two-hybrid (identification via RPA3 bait), co-immunoprecipitation, multi-step chromatographic purification, yeast null mutation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, purification, genetic viability assay); replicated across organisms\",\n      \"pmids\": [\"9774387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RUVBL1 (TIP49a/TIP49) is an ATP-dependent DNA helicase with ssDNA-stimulated ATPase activity that unwinds DNA duplexes in the 3' to 5' direction, as established by in vitro enzyme assays with purified recombinant protein.\",\n      \"method\": \"In vitro ATPase assay, DNA helicase assay, UV cross-linking, recombinant protein purification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, multiple enzymatic assays; replicated by related studies\",\n      \"pmids\": [\"10336418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RUVBL1 (TIP49a) and RUVBL2 (TIP49b) bind each other and are found together in the same ~700 kDa complex in cells. TIP49b has opposite DNA helicase polarity (5' to 3') compared to TIP49a (3' to 5'), and TIP49b does not complement the TIP49a yeast null mutation, indicating non-redundant functions.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration (complex size), in vitro ATPase and helicase assays, yeast complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assays, Co-IP complex formation, genetic complementation; multiple orthogonal methods\",\n      \"pmids\": [\"10428817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RUVBL1 (Pontin52) and RUVBL2 (Reptin52) interact with each other and both bind beta-catenin and TBP, but act antagonistically on beta-catenin/TCF transactivation in reporter gene assays. This antagonism is conserved in Drosophila (dpontin vs. dreptin in Wingless signaling).\",\n      \"method\": \"Reporter gene assay (transactivation), co-immunoprecipitation, Drosophila in vivo genetics\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional reporter assay, cross-species genetic validation; multiple orthogonal approaches\",\n      \"pmids\": [\"11080158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RUVBL1 (TIP49a) functions as a plasminogen-binding protein on the U937 cell surface via a C-terminal lysine; it binds human plasminogen with a Kd of 0.57 μM and enhances plasminogen activation 8-fold, as demonstrated by ligand blotting and plasminogen activation assays.\",\n      \"method\": \"2D gel electrophoresis, ligand blotting with 125I-plasminogen, carboxypeptidase B sensitivity assay, kinetic binding assay, plasminogen activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab\",\n      \"pmids\": [\"11027681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RUVBL1 (TIP49) modulates c-Myc-mediated apoptosis and also binds the E2F1 transactivation domain to modulate E2F1-dependent transforming and apoptotic activities, while the related factor TRRAP does not affect apoptosis. This distinguishes RUVBL1 as a specific cofactor for these transcription factors.\",\n      \"method\": \"Co-immunoprecipitation (E2F1 binding), functional apoptosis assays, dominant-negative mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding, functional assays with dominant-negative mutant, single lab\",\n      \"pmids\": [\"12185582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RUVBL1 (TIP49) ATPase activity is required for beta-catenin-mediated neoplastic transformation and activation of TCF-dependent genes. An ATPase-deficient mutant (TIP49D302N) inhibited these activities. RUVBL1 was found in complexes with TIP60, TRRAP, and BAF53 chromatin-remodeling factors at the ITF-2 promoter, and its inhibition reduced histone acetylation near TCF-binding sites.\",\n      \"method\": \"ATPase-deficient mutant (D302N) expression, reporter gene assay, siRNA knockdown, chromatin immunoprecipitation (ChIP), co-immunoprecipitation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis, ChIP, Co-IP, siRNA, multiple orthogonal methods in one study\",\n      \"pmids\": [\"14695187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RUVBL1 associates with alpha- and gamma-tubulin and localizes to the centrosome and mitotic spindle during mitosis, where its topology varies with mitotic stage. RUVBL1 promotes in vitro tubulin assembly.\",\n      \"method\": \"Protein affinity chromatography, co-immunoprecipitation, confocal immunofluorescence microscopy, GST pulldown, in vitro tubulin assembly assay\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pulldown, imaging, and functional assay; single lab\",\n      \"pmids\": [\"14506706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of human RuvBL1 hexamer was solved at 2.2 Å resolution in complex with ADP. The structure revealed three domains: domains I and III mediate ATP binding/hydrolysis, while domain II (unique to eukaryotes, absent from bacterial RuvB) is a novel DNA/RNA-binding domain. RuvBL1 binds single-stranded DNA/RNA and double-stranded DNA, but shows only marginal ATPase activity in isolation, suggesting requirement for cofactors.\",\n      \"method\": \"X-ray crystallography (2.2 Å), DNA binding assays, ATPase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with biochemical validation, multiple assays\",\n      \"pmids\": [\"17060327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human TIP48 and TIP49 form a stable equimolar dodecameric complex (two stacked hexameric rings) with synergistic ATPase activity. Both proteins are required for ATPase activity (catalytic mutants in either abolish activity). No DNA helicase or branch migration activity was detected in the reconstituted complex.\",\n      \"method\": \"In vitro reconstitution, ATPase assay, ATPase-deficient mutants, negative stain electron microscopy (3D reconstruction at 20 Å)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution, mutagenesis, ATPase assay, and EM structure in one study\",\n      \"pmids\": [\"17157868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human RUVBL1 (Rvb1) is required for the histone acetyltransferase (HAT) activity of the Tip60/NuA4 complex but not for Ino80 or SRCAP complexes. RUVBL1 depletion increases persistence of phospho-H2AX after DNA damage, and this phenotype is phenocopied by Tip60 depletion. Histone H4 acetylation by Tip60 is required prior to dephosphorylation of phospho-H2AX.\",\n      \"method\": \"siRNA knockdown, in vitro HAT activity assay, immunofluorescence, H4 acetylation assay, epistasis between Rvb1 and Tip60/Ino80/SRCAP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro HAT activity assay, genetic epistasis, multiple knockdown comparisons, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18285460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Rvb1 and Rvb2 form a heterohexameric ring with enhanced ATPase activity compared to individual proteins; ATPase is further stimulated by dsDNA with 5' or 3' overhangs. The complex exhibits ATP-dependent DNA helicase activity preferring 5' to 3' unwinding.\",\n      \"method\": \"In vitro reconstitution, ATPase assay, electron microscopy, DNA helicase assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, multiple enzymatic assays, EM structural analysis\",\n      \"pmids\": [\"18234224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RUVBL1 depletion reduced RAD51 recruitment to chromatin and nuclear foci formation after DSBs and interstrand crosslinks by ~50%, without affecting DNA damage checkpoint signaling (H2AX phosphorylation). Histone deacetylase inhibitor treatment restored RAD51 foci, linking RUVBL1 to chromatin modification-dependent homologous recombination repair.\",\n      \"method\": \"siRNA knockdown, RAD51 foci immunofluorescence, chromatin fractionation, HDAC inhibitor rescue experiment\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined cellular phenotype, pharmacological rescue; single lab\",\n      \"pmids\": [\"18834951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TIP48 and TIP49 play a major role in catalyzing H2A acetylation-induced H2A.Z exchange into nucleosomes via their ATPase activities. TIP60-mediated acetylation of nucleosomal H2A specifically facilitates the action of the complex containing TIP48/TIP49 in the H2A.Z exchange reaction.\",\n      \"method\": \"Purification of H2A.Z-interacting complexes, in vitro H2A.Z exchange assay, TIP60 HAT assay, ATPase-dependent mechanistic dissection\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted exchange assay, complex purification, enzymatic dissection; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19696079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RUVBL1 and RUVBL2 associate with each PIKK family member (ATM, ATR, mTOR, DNA-PKcs, SMG-1, TRRAP), control PIKK mRNA and protein abundance upon knockdown, and promote the assembly of SMG-1-containing mRNA surveillance complexes in the cytoplasm during nonsense-mediated mRNA decay (NMD).\",\n      \"method\": \"Co-immunoprecipitation (RUVBL1/2 with PIKKs), siRNA knockdown (PIKK abundance and NMD), mRNP complex assembly assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP across multiple PIKKs, siRNA with functional NMD readout, multiple orthogonal methods\",\n      \"pmids\": [\"20371770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RUVBL1 represses p53 transcription by binding to the p53 promoter, interfering with RNF20/hBRE1-mediated histone H2B monoubiquitination, and promoting PAF1-mediated histone H3K9 trimethylation. This mechanism underlies RUVBL1's ability to block p53-mediated apoptosis downstream of EHF transcription factor activation.\",\n      \"method\": \"ChIP, co-immunoprecipitation, siRNA knockdown, reporter assay, histone modification analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, siRNA, single lab with multiple methods\",\n      \"pmids\": [\"21617703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RuvBL1-RuvBL2 heterodimeric complex forms a dodecamer of two heterohexameric rings with alternating RUVBL1/RUVBL2 subunits bound to ADP/ATP. Truncation of domain II substantially increases ATPase activity, and domain II auto-inhibits helicase activity—showing that in vivo activities are regulated by cofactors via domain II conformational changes.\",\n      \"method\": \"X-ray crystallography (dodecamer with truncated DII), SAXS, ATPase assay, helicase assay\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, SAXS validation, multiple enzymatic assays in one study\",\n      \"pmids\": [\"21933716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hsp90 forms complexes with the RUVBL1/2 complex and the Tel2 complex, and Hsp90 inhibition reduces abundance of all PIKK family members and suppresses PIKK-mediated signaling, demonstrating that Hsp90 regulates PIKKs together with RUVBL1/2.\",\n      \"method\": \"Co-immunoprecipitation, Hsp90 inhibitor treatment, immunoblot for PIKK levels\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pharmacological inhibition, single lab\",\n      \"pmids\": [\"21951644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cryo-EM of the human RuvBL1-RuvBL2 complex revealed two coexisting conformations (compact and stretched) driven by movements in domain II (DII). DII domains connect the AAA+ core and expose DNA-binding regions, suggesting that these conformational transitions regulate the activity of RUVBL1-RUVBL2-containing complexes.\",\n      \"method\": \"Cryo-electron microscopy (~15 Å), image classification, nucleic acid binding analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural analysis with functional interpretation, single lab but rigorous structural method\",\n      \"pmids\": [\"23002137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The TTT-RUVBL1/2 complex (TELO2-TTI1-TTI2 plus RUVBL1/2) is required for mTORC1 assembly into obligate dimers, its lysosomal localization, and its interaction with Rag GTPases. Energy depletion (loss of ATP from glucose/glutamine) disassembles and represses the TTT-RUVBL complex, thereby impairing mTORC1 function.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, lysosome fractionation, AMPK/TSC epistasis analysis, metabolic flux assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"23142078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RuvbL1 and RuvbL2 function as disaggregases: they directly interact with aggregated substrate synphilin-1 near the opening of the central channel of the barrel structure, polypeptides with unfolded structures and amyloid fibrils stimulate RuvbL ATPase activity, and the complex promotes disassembly of protein aggregates and aggresome formation.\",\n      \"method\": \"siRNA screen, Co-IP (synphilin-1 interaction), ATPase stimulation assay (amyloid fibrils), aggregate disaggregation assay, yeast genetic studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ATPase assay with amyloid substrates, Co-IP, functional disaggregation assay, genetic analysis in yeast\",\n      \"pmids\": [\"26303906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RuvBL1 and RuvBL2 co-purify with the Fanconi anemia (FA) core complex under native conditions, and depletion of RuvBL1-RuvBL2 leads to co-depletion of the FA core complex, causes DNA crosslinker sensitivity, chromosomal instability, and defective FA pathway activation. Conditional Ruvbl1 knockout in mouse hematopoietic cells causes aplastic anemia.\",\n      \"method\": \"Affinity purification-MS, co-immunoprecipitation, siRNA depletion, mouse conditional knockout, DNA crosslinker sensitivity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AP-MS, Co-IP, in vivo mouse KO with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"25428364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 oligomers preferentially interact with RUVBL1 (rather than RUVBL2) and DNA binding by YY1 oligomers is enhanced in the presence of RuvBL1-RuvBL2. YY1 and the ATPase activity of RUVBL2 are required for RAD51 foci formation during homologous recombination.\",\n      \"method\": \"Co-immunoprecipitation, electron microscopy, in vitro DNA binding assay, functional HR assay (RAD51 foci)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro binding assay, functional HR readout; single lab\",\n      \"pmids\": [\"24990942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RUVBL1 localizes to the cytoplasm in pancreatic cancer cells where it directly binds filamentous actin (F-actin), increases G-actin concentration in cell protrusions, promotes peripheral actin polymerization, and thereby drives formation of membrane protrusions to enhance cancer cell invasion.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, confocal microscopy (F-actin colocalization), motility/invasion assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, localization by microscopy, functional invasion assay; single lab\",\n      \"pmids\": [\"24728183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RUVBL1 localizes to structures of the mitotic spindle apparatus in anaphase-to-telophase transition, partially co-localizing with PLK1. PLK1 phosphorylates RUVBL1 (but not RUVBL2) in vitro, and they physically associate in vivo. siRNA knockdown of RuvBL proteins causes chromosome alignment and segregation defects, and the ATPase activity of RUVBL1 is indispensable for cell proliferation.\",\n      \"method\": \"Immunofluorescence microscopy, in vitro kinase assay (PLK1), co-immunoprecipitation, siRNA knockdown, ATPase-deficient mutant complementation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, Co-IP, live imaging, siRNA; single lab, multiple methods\",\n      \"pmids\": [\"26201077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A domain within the INO80 ATPase subunit (Ino80INS) stimulates Rvb1/2 ATPase activity 16-fold and promotes dodecamerization. Cryo-EM and mass spectrometry show Ino80INS binds asymmetrically at the dodecamerization interface, creating a conformationally flexible dodecamer that collapses into hexamers upon ATP addition, demonstrating chaperone-like cycling behavior.\",\n      \"method\": \"ATPase assay, cryo-EM, crosslinking mass spectrometry, integrative structural modeling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with ATPase assay, cryo-EM structure, MS; multiple orthogonal methods in one study\",\n      \"pmids\": [\"28591576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRMT5 methylates RUVBL1 at arginine R205, which is required for TIP60-dependent mobilization of 53BP1 from DSBs and promotes homologous recombination. PRMT5-directed methylation of RUVBL1 is critically required for TIP60 acetyltransferase activity and histone H4K16 acetylation, which facilitates 53BP1 displacement. Methylation did not affect ATM activation.\",\n      \"method\": \"In vitro methyltransferase assay (PRMT5 on RUVBL1), mutant RUVBL1 (R205 site), TIP60 HAT activity assay, ChIP (H4K16Ac, 53BP1 foci), siRNA\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with specific mutant, ChIP, HAT activity assay; multiple orthogonal methods, rigorous controls\",\n      \"pmids\": [\"28238654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The R2TP/Prefoldin-like complex interacts with the U5 snRNP, mediated primarily by the uncharacterized factor ZNHIT2. ZNHIT2 directly binds RUVBL2's DII domain; disruption of ZNHIT2 or RUVBL2 expression impacts U5 snRNP protein composition, implicating RUVBL1/2 in U5 snRNP assembly.\",\n      \"method\": \"Affinity purification-MS (multi-target), co-immunoprecipitation, siRNA knockdown with snRNP composition analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS, Co-IP, siRNA KD with complex composition readout; single lab\",\n      \"pmids\": [\"28561026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adenovirus E1A binds RUVBL1 via the C-terminus of E1A and is recruited to RUVBL1-regulated promoters in an interferon-dependent manner, suppressing interferon-stimulated gene transcriptional activation. Depletion of RUVBL1 impairs adenovirus growth but does not affect viral genome replication or S-phase induction.\",\n      \"method\": \"Co-immunoprecipitation (E1A-RUVBL1), ChIP, siRNA knockdown, viral growth assay, domain mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ChIP at promoters, functional viral assay; single lab\",\n      \"pmids\": [\"28122980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RUVBL1 interacts with DNAAF1 and IFT88 (ciliary intraflagellar transport protein). Loss of RUVBL1 perturbs DNAAF1/IFT88 co-localization, and RUVBL1 orthologs show asymmetric left-sided distribution at the embryonic node and zebrafish Kupffer's vesicle. Conditional Ruvbl1 deletion in tubular epithelial cells causes renal failure with fewer ciliated cells; deletion in motile-ciliated cells causes hydrocephalus. Cilia of Ruvbl1-negative cells lack crucial ciliary proteins, consistent with cytoplasmic pre-assembly of ciliary complexes.\",\n      \"method\": \"Co-immunoprecipitation (RUVBL1-DNAAF1-IFT88), conditional mouse knockout (renal epithelium, motile cilia), immunofluorescence, zebrafish asymmetry assay\",\n      \"journal\": \"Human molecular genetics / Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in two cell types with distinct phenotypes, Co-IP, live organism localization; multiple orthogonal methods\",\n      \"pmids\": [\"29228333\", \"29959317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The cryo-EM structure of the human R2TP co-chaperone complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) reveals that binding of PIH1D1 to the DII domain of RUVBL2 induces conformational rearrangements that destabilize an N-terminal segment of RUVBL2 acting as a gatekeeper to nucleotide exchange, thereby regulating RUVBL2 ATPase activity. This DII-mediated nucleotide access mechanism is proposed to be general.\",\n      \"method\": \"Cryo-EM structure determination, biochemical validation of conformational changes\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mechanistic biochemical validation, single lab\",\n      \"pmids\": [\"31049401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CB-6644 is an allosteric small-molecule inhibitor of the RUVBL1/2 ATPase complex; drug-resistant clones carry mutations in RUVBL1 or RUVBL2, confirming on-target mechanism. Inhibition of RUVBL1/2 ATPase activity leads to cancer cell death and reduced tumor growth in AML and multiple myeloma xenograft models.\",\n      \"method\": \"In vitro ATPase inhibition assay, acquired resistance mutation mapping, xenograft tumor models\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic inhibition, resistance mutation validation (on-target), in vivo xenograft; multiple methods\",\n      \"pmids\": [\"30640450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RUVBL1/2 ATPase activity is necessary for maturation/dissociation of the PAQosome (large RUVBL1/2-dependent multiprotein complex) and for DNA replication; its inhibition causes S-phase arrest and replication catastrophe in cancer cells.\",\n      \"method\": \"RUVBL1/2 ATPase inhibitor treatment, PAQosome complex analysis, S-phase flow cytometry, replication assay\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition, complex composition assay, cell cycle readout; single lab\",\n      \"pmids\": [\"31883965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RUVBL1 promotes the RAF/MEK/ERK pathway by binding C-RAF and inhibiting phosphorylation of C-RAF at serine 259, thereby activating the pathway to promote lung cancer cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation (RUVBL1-CRAF), immunoblot for pS259-CRAF, RUVBL1 knockout (cell proliferation/invasion assay), xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation analysis, KO functional assay; single lab\",\n      \"pmids\": [\"29545175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RUVBL1-RUVBL2 complex controls assembly and composition of the gamma-tubulin ring complex (γTuRC) in human cells. RUVBL1/2 interacts with γTuRC subcomplexes but is absent from fully assembled γTuRC. Purified, RUVBL1/2-assembled recombinant γTuRC has microtubule nucleation activity and resembles native γTuRC by cryo-EM (~4.0 Å).\",\n      \"method\": \"siRNA knockdown (γTuRC assembly), heterologous coexpression reconstitution, cryo-EM structure (~4.0 Å), co-immunoprecipitation, microtubule nucleation assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of γTuRC assembly, cryo-EM structural validation, functional nucleation assay, KD in cells; multiple orthogonal methods\",\n      \"pmids\": [\"33355144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM reveals that DHX34, an RNA helicase regulating NMD initiation, directly interacts with RUVBL1-RUVBL2 in vitro and in cells. DHX34 binding induces extensive conformational changes in N-termini of every RUVBL2 subunit, stabilizing a conformation that cannot bind nucleotide, downregulating RUVBL2 ATP hydrolysis. ATPase-deficient mutants show DHX34 acts exclusively on RUVBL2 subunits.\",\n      \"method\": \"Cryo-EM structure, in vitro binding assay, co-immunoprecipitation, ATPase-deficient mutant analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural determination, in vitro biochemical validation, mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"33205750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Both excess and depletion of RUVBL1 impede DNA replication through transcription-dependent mechanisms. RUVBL1 overexpression increases c-Myc-dependent RNAPII pause release and transcription; RUVBL1 depletion increases Rpb1 ubiquitination and reduces RNAP II mobility, causing stalled RNAPII. Both states result in replication-transcription interference.\",\n      \"method\": \"siRNA knockdown, RUVBL1 overexpression, pSer2 CTD immunoblot, Rpb1 ubiquitination assay, FRAP, replication fork rate measurement\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary functional assays, single lab\",\n      \"pmids\": [\"32846207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NOPCHAP1 (C12ORF45) acts as a PAQosome cofactor that bridges NOP58 to the PAQosome by making direct physical interactions with the CC-NOP domain of NOP58 and domain II of RUVBL1/2 AAA+ ATPases. NOPCHAP1 interaction with RUVBL1/2 is disrupted upon ATP binding, suggesting a nucleotide-regulated client-loading mechanism for C/D snoRNP biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro direct binding assay, ATP competition assay, NOP58 KO cell analysis, proteomic pulldown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay, Co-IP, ATP-dependent release mechanism, domain-level specificity; multiple orthogonal methods\",\n      \"pmids\": [\"33367824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RUVBL1 interacts with SMCHD1 and is present at D4Z4 chromatin; loss of RUVBL1 further derepresses DUX4 in FSHD myocytes, placing RUVBL1 in a SMCHD1-dependent chromatin repression pathway at the D4Z4 locus.\",\n      \"method\": \"Quantitative proteomics (SMCHD1 interactome), ChIP, siRNA knockdown, DUX4 derepression assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS interactome, ChIP, functional KD assay; single lab\",\n      \"pmids\": [\"34880314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rvb1/Rvb2 are enriched at promoters and mRNAs of alternative glucose metabolism genes during starvation. Engineered Rvb1/Rvb2 tethering to mRNAs is sufficient to sequester those mRNAs into mRNP granules, repress their translation, and drive further transcriptional upregulation of target genes, demonstrating coupling of transcription, mRNA localization, and translation.\",\n      \"method\": \"ChIP, RNA immunoprecipitation, mRNA tethering (engineered binding), stress granule imaging, ribosome profiling, genetic depletion\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered tethering experiment, ChIP, multiple readouts; single lab in yeast model\",\n      \"pmids\": [\"36107469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC00839 (lncRNA) recruits RUVBL1 to the Tip60 complex and increases its acetyltransferase activity; the complex is guided to the NRF1 promoter and promotes H4K5 and H4K8 acetylation to upregulate NRF1 expression.\",\n      \"method\": \"Co-immunoprecipitation (LINC00839-RUVBL1-TIP60), ChIP (H4K5Ac, H4K8Ac at NRF1 promoter), siRNA/shRNA knockdown, reporter assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, functional rescue; single lab\",\n      \"pmids\": [\"35876654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUVBL1/2 inhibition significantly reduces histone H3K4me3 at the Nos2 and Il6 promoters and diminishes NF-κB recruitment to corresponding enhancers, demonstrating that RUVBL1/2 regulate macrophage pro-inflammatory gene expression through epigenetic H3K4 trimethylation.\",\n      \"method\": \"siRNA knockdown, RUVBL1/2 pharmacological inhibition, ChIP (H3K4me3, NF-κB), transcriptome analysis, functional NO production assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with histone modification readout, pharmacological inhibition, multiple gene targets; single lab\",\n      \"pmids\": [\"34276666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DPCD directly interacts with RUVBL1 and RUVBL2 in vitro and in cells, predominantly via DII domains of RUVBL1/2. DPCD binding disrupts the dodecameric state of the RUVBL1/2 complex.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro direct binding assay, SAXS, structural mass spectrometry, electron microscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding, SAXS, EM structural analysis, Co-IP; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35901867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GART methylates RUVBL1 at K7, enhancing RUVBL1 protein stability. This stabilization aberrantly activates the Wnt/β-catenin signaling pathway to induce tumor stemness in colorectal cancer.\",\n      \"method\": \"In vitro methyltransferase assay (GART on RUVBL1 K7), site-directed mutagenesis (E948 active site), co-immunoprecipitation, protein stability assay, β-catenin pathway reporter\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methyltransferase assay, active site mutant, K7 site identification; single lab\",\n      \"pmids\": [\"37439412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RUVBL1 controls MYC chromatin binding and modulates MYC-driven EEF1A1 expression and protein synthesis. A high-density CRISPR gene body scan identified the MYC-interacting residue(s) in RUVBL1 critical for this function.\",\n      \"method\": \"CRISPR screen (gene body scan), ChIP (MYC binding), RUVBL1 suppression (shRNA/CRISPR), protein synthesis assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR domain scan, ChIP, functional protein synthesis readout; single lab\",\n      \"pmids\": [\"37075745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DTL ubiquitinates RUVBL1 and facilitates RUVBL1 binding to RUVBL2 and β-catenin. Ubiquitinated RUVBL1 promotes transcriptional regulation of NHEJ repair pathway genes via the RUVBL1/2–β-catenin complex, while attenuating TIP60-mediated H4K16 acetylation and HR repair, thereby enhancing radioresistance.\",\n      \"method\": \"Co-immunoprecipitation (DTL-RUVBL1, RUVBL1-RUVBL2-β-catenin), ubiquitination assay, ChIP (NHEJ gene promoters, H4K16Ac), siRNA/knockdown, in vitro and in vivo radioresistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay, Co-IP, ChIP; single lab, multiple methods\",\n      \"pmids\": [\"38609375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RUVBL1 is required for MYC to establish oncogenic and immunoevasive gene expression in pancreatic ductal adenocarcinoma (PDAC). Degradation of RUVBL1 (auxin-degron system) arrests cancer but not untransformed cells and causes complete tumor regression in mice, preceded by immune cell infiltration.\",\n      \"method\": \"shRNA library screen (in vitro and in vivo), auxin-degron targeted degradation, gene expression analysis, in vivo PDAC mouse tumor model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic screen, targeted protein degradation, in vivo tumor regression; multiple orthogonal in vitro and in vivo methods\",\n      \"pmids\": [\"38821858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RUVBL1 promotes enzalutamide resistance in prostate cancer by localizing to the cytoplasm upon enzalutamide treatment, enhancing recruitment of CRAF to plexin A1 (PLXNA1), and activating the downstream MAPK pathway.\",\n      \"method\": \"Co-immunoprecipitation (RUVBL1-CRAF-PLXNA1), subcellular fractionation (cytoplasmic RUVBL1), siRNA/CB-6644 inhibition, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, fractionation, pharmacological/genetic KD; single lab\",\n      \"pmids\": [\"35508542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RUVBL1/2 reciprocally interact with YTHDF1 at 40S translation initiation complexes (identified by Co-IP and mass spectrometry). RUVBL1/2 loss stalls YTHDF1-driven oncogenic translation and nascent protein biosynthesis; ribosome sequencing shows impaired MAPK, RAS, and PI3K-AKT signaling translation upon RUVBL1/2 depletion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ribosome sequencing, siRNA knockdown, polysome profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with MS, ribosome sequencing, multiple functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"38900944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RUVBL1 is an essential AAA+ ATPase that forms a heterohexameric (and dodecameric) ring complex with RUVBL2; its ATPase activity—regulated allosterically by domain II movements, client proteins (e.g., Ino80INS, DHX34, PIH1D1), and post-translational modifications including PLK1 phosphorylation (at mitosis), PRMT5-mediated R205 methylation (promoting TIP60 HAT activity and HR repair), GART-mediated K7 methylation (stabilizing the protein), and DTL-mediated ubiquitination (shifting it toward NHEJ)—underpins its roles as a scaffold and assembly chaperone for multiple nuclear complexes (TIP60/NuA4 HAT, INO80, SWR-C/SRCAP, R2TP co-chaperone, mTORC1-TTT, FA core complex, γTuRC, U5 snRNP, snoRNPs), where it facilitates H2A.Z exchange, histone acetylation, DNA damage repair (HR and NHEJ), beta-catenin/TCF transcription, PIKK assembly and NMD, cytoplasmic protein disaggregation, mitotic spindle function, and ciliogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RUVBL1 is an essential AAA+ ATPase that pairs with RUVBL2 to form heterohexameric and stacked dodecameric ring structures, serving as a scaffold and assembly chaperone for numerous nuclear and cytoplasmic multiprotein machines [#4, #11, #2]. Each protomer comprises ATP-binding/hydrolysis domains (I and III) and a eukaryote-specific, nucleic-acid-binding domain II that auto-inhibits and allosterically gates ATPase and helicase activity through large conformational transitions [#10, #18, #20]; client proteins and cofactors bind domain II to license catalysis and remodel oligomeric state, as shown for Ino80INS, the R2TP factors PIH1D1 and RPAP3, DHX34, NOPCHAP1, and DPCD [#27, #32, #37, #39, #44]. Although isolated RUVBL1 was first characterized as an ssDNA-stimulated 3'-to-5' ATP-dependent DNA helicase, the assembled RUVBL1/2 complex shows only marginal intrinsic helicase activity and acts principally as an assembly chaperone whose ATPase cycle drives client loading and complex maturation [#3, #11, #34]. Through this activity RUVBL1/2 builds and regulates chromatin-modifying and remodeling complexes—notably enabling TIP60/NuA4 histone acetyltransferase activity and ATPase-dependent H2A.Z exchange into nucleosomes [#12, #15]—and these functions underpin DNA double-strand break repair by both homologous recombination and non-homologous end joining, with PRMT5-mediated R205 methylation of RUVBL1 promoting TIP60 HAT activity, H4K16 acetylation and 53BP1 displacement to favor HR, and DTL-mediated ubiquitination shifting the balance toward NHEJ [#28, #14, #47]. RUVBL1/2 is the assembly engine of broader R2TP/PAQosome chaperone activity required for PIKK stability and nonsense-mediated decay, mTORC1 dimerization and lysosomal localization, U5 snRNP and C/D snoRNP biogenesis, the Fanconi anemia core complex, and the γ-tubulin ring complex, and it supports mitotic spindle function and ciliogenesis [#16, #21, #29, #39, #23, #36, #26, #31]. In transcription it acts as a cofactor for the β-catenin/TCF, MYC and E2F1 programs and, with cytoplasmic disaggregase activity toward amyloid and aggregated substrates, links the complex to proteostasis [#1, #5, #8, #46, #22]. RUVBL1/2 ATPase activity is required for cancer cell proliferation and is druggable by the allosteric inhibitor CB-6644, with MYC-driven tumors being acutely dependent on RUVBL1 [#33, #48].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that RUVBL1 is a nuclear, RuvB-homologous protein physically linked to transcription machinery and essential for viability, framing it as a conserved enzyme with a core cellular role.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP placing it in the RNA Pol II holoenzyme, plus a lethal yeast null mutation; parallel work mapping its binding to β-catenin and TBP\",\n      \"pmids\": [\"9774387\", \"9843967\", \"9196036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical activity of the protein\", \"Did not identify the obligate RUVBL2 partner\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the biochemical activity by showing recombinant RUVBL1 is an ATP-dependent 3'-to-5' DNA helicase and that it forms a ~700 kDa complex with the opposite-polarity, non-redundant RUVBL2.\",\n      \"evidence\": \"In vitro ATPase/helicase assays on purified protein, Co-IP, gel filtration, and yeast complementation\",\n      \"pmids\": [\"10336418\", \"10428817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Helicase activity later not detected in the reconstituted human complex\", \"Physiological substrate of the helicase activity unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed RUVBL1 and RUVBL2 act antagonistically on β-catenin/TCF transactivation, establishing the paralog pair as functionally distinct regulators of Wnt-pathway transcription conserved to Drosophila.\",\n      \"evidence\": \"Reporter transactivation assays, Co-IP, and Drosophila genetics\",\n      \"pmids\": [\"11080158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of antagonism at chromatin not defined\", \"Did not link to a specific chromatin-modifying complex\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected RUVBL1 ATPase activity to chromatin-templated transcription, showing it operates within TIP60/TRRAP/BAF53 complexes to drive histone acetylation and β-catenin-mediated transformation.\",\n      \"evidence\": \"ATPase-dead D302N mutant, ChIP at the ITF-2 promoter, siRNA, and Co-IP; plus centrosome/spindle association and tubulin assembly assays\",\n      \"pmids\": [\"14695187\", \"14506706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate scaffolding from catalytic contributions to acetylation\", \"Mitotic role only correlative at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a complex-specific requirement: RUVBL1 is needed for TIP60/NuA4 HAT activity (not INO80 or SRCAP) and links chromatin acetylation to DNA damage resolution, while the yeast Rvb1/Rvb2 hexamer was shown to be an enhanced ATPase/helicase.\",\n      \"evidence\": \"siRNA with in vitro HAT assays, epistasis between Rvb1/Tip60/Ino80/SRCAP, phospho-H2AX persistence, and RAD51 foci with HDAC-inhibitor rescue; in vitro reconstitution of yeast heterohexamer\",\n      \"pmids\": [\"18285460\", \"18834951\", \"18234224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling acetylation to phospho-H2AX dephosphorylation incomplete\", \"Direct enzymatic role in HR not isolated from chromatin remodeling\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated the catalytic mechanism by which the TIP48/TIP49 ATPases drive TIP60-acetylation-dependent H2A.Z deposition into nucleosomes, defining a histone-exchange function.\",\n      \"evidence\": \"Purification of H2A.Z-interacting complexes with in vitro exchange and TIP60 HAT assays and ATPase-dependent dissection\",\n      \"pmids\": [\"19696079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of nucleosome engagement not resolved\", \"In vivo locus-specificity of exchange not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the structural logic of regulation: dodecameric assembly with domain II auto-inhibiting helicase activity, indicating in vivo function is gated by cofactors acting on DII.\",\n      \"evidence\": \"Crystallography of dodecamer with truncated DII, SAXS, and ATPase/helicase assays; earlier 2.2 Å hexamer structure defining DII as the nucleic-acid-binding domain\",\n      \"pmids\": [\"21933716\", \"17060327\", \"17157868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of physiological DII-acting cofactors not yet defined\", \"Link between conformational state and specific complex assembly unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established RUVBL1/2 as the core of the R2TP-related TTT chaperone that assembles PIKKs and mTORC1, coupling complex assembly to nutrient/energy status, and visualized the DII-driven conformational equilibrium.\",\n      \"evidence\": \"Co-IP across PIKK family members with NMD readout, TTT-mTORC1 fractionation/epistasis and metabolic flux assays, Hsp90 inhibition, and cryo-EM of compact/stretched states\",\n      \"pmids\": [\"20371770\", \"23142078\", \"21951644\", \"23002137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of client handoff to mature complexes unresolved\", \"How energy status mechanically disassembles the complex not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened the assembly-chaperone role to the Fanconi anemia core complex and DNA crosslink repair, with in vivo knockout phenotypes, and implicated YY1 and cytoplasmic actin in additional functions.\",\n      \"evidence\": \"AP-MS/Co-IP with FA core, siRNA co-depletion, mouse conditional Ruvbl1 knockout causing aplastic anemia, plus YY1 EM/HR assays and F-actin binding/invasion assays\",\n      \"pmids\": [\"25428364\", \"24990942\", \"24728183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RUVBL1/2 directly chaperones FA assembly versus stabilizes it not fully separated\", \"Cytoplasmic actin and YY1 roles rest on single-lab evidence\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-translational control of RUVBL1 in DNA repair, with PRMT5-mediated R205 methylation enabling TIP60 HAT activity and HR, and resolved client-driven dodecamerization mechanistically via Ino80INS.\",\n      \"evidence\": \"In vitro methyltransferase assay with R205 mutant, HAT/ChIP assays for H4K16Ac and 53BP1; cryo-EM/XL-MS of Ino80INS-stimulated Rvb1/2; AP-MS linking R2TP to U5 snRNP via ZNHIT2\",\n      \"pmids\": [\"28238654\", \"28591576\", \"28561026\", \"28122980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes reversing R205 methylation unknown\", \"How DII-binding clients select among many complexes not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the general DII-gated nucleotide-exchange mechanism and validated RUVBL1/2 ATPase as a druggable, essential activity for tumor growth and DNA replication.\",\n      \"evidence\": \"Cryo-EM of R2TP (RPAP3-PIH1D1) showing DII-induced gatekeeper destabilization; CB-6644 allosteric inhibition with on-target resistance mutations and xenograft regression; PAQosome maturation and replication-catastrophe assays; C-RAF S259 pathway work\",\n      \"pmids\": [\"31049401\", \"30640450\", \"31883965\", \"29545175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single allosteric mechanism selectively affects diverse client complexes unresolved\", \"Replication phenotype mixes direct and transcription-coupled effects\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the assembly-chaperone paradigm to γTuRC assembly, ciliary complex pre-assembly, and disaggregase activity, and resolved how the NMD helicase DHX34 down-tunes RUVBL2 ATPase via N-terminal conformational change.\",\n      \"evidence\": \"γTuRC reconstitution with cryo-EM and nucleation assays; conditional Ruvbl1 knockouts causing renal failure and hydrocephalus with cilia defects; cryo-EM of DHX34-RUVBL1/2; disaggregation/ATPase-stimulation assays with amyloid substrates; transcription-replication interference analysis\",\n      \"pmids\": [\"33355144\", \"29228333\", \"29959317\", \"33205750\", \"26303906\", \"32846207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How one ATPase serves cytoplasmic disaggregation and nuclear assembly is unclear\", \"Selectivity for individual ciliary/spindle clients not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RUVBL1 as a MYC-cooperating dependency required for oncogenic and immunoevasive gene programs and oncogenic translation, and added further PTM control (GART K7 methylation, DTL ubiquitination) tuning Wnt signaling and repair-pathway choice.\",\n      \"evidence\": \"Auxin-degron and shRNA screens with in vivo PDAC regression, CRISPR gene-body MYC-interaction mapping with ChIP, YTHDF1/40S Co-IP-MS with ribosome sequencing; in vitro K7-methyltransferase and DTL-ubiquitination assays with ChIP and pathway readouts\",\n      \"pmids\": [\"38821858\", \"37075745\", \"38900944\", \"37439412\", \"38609375\", \"35876654\", \"34276666\", \"34880314\", \"35508542\", \"36107469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYC dependency reflects direct chromatin scaffolding versus chaperone-mediated complex assembly is unresolved\", \"Several PTM/cancer findings rest on single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single RUVBL1/2 ATPase cycle and DII-gated conformational switch achieve selective, ordered assembly of dozens of distinct nuclear and cytoplasmic client complexes remains the central open mechanistic question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model linking client identity at DII to a defined ATPase output\", \"Rules governing partition between disaggregation, histone exchange, and chaperone roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 4, 11, 13, 18, 26, 33, 34]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 4, 11, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 10, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [22, 27]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [27, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 22, 25, 49]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9, 36]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9, 25]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 12, 15, 28, 42, 43]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14, 23, 28, 47]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 8, 17, 46]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 21, 29, 39, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [16, 29, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 21, 35, 49]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [26, 34, 36]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [34, 38]}\n    ],\n    \"complexes\": [\n      \"R2TP/PAQosome (RUVBL1-RUVBL2-RPAP3-PIH1D1)\",\n      \"TIP60/NuA4 HAT complex\",\n      \"TTT-RUVBL1/2 (mTORC1 assembly)\",\n      \"Fanconi anemia core complex\"\n    ],\n    \"partners\": [\n      \"RUVBL2\",\n      \"TIP60\",\n      \"PIH1D1\",\n      \"DHX34\",\n      \"CTNNB1\",\n      \"TBP\",\n      \"NOPCHAP1\",\n      \"DPCD\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}