{"gene":"RUVBL2","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1999,"finding":"TIP49b (RUVBL2) is an ssDNA-stimulated ATPase and ATP-dependent DNA helicase with 5'-to-3' polarity (opposite to TIP49a/RUVBL1). TIP49b and TIP49a physically interact and co-purify in the same ~700 kDa complex in cells.","method":"Enzyme assays (ATPase, helicase), co-immunoprecipitation, size-exclusion chromatography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro enzymatic assays plus co-purification, single lab with multiple orthogonal methods","pmids":["10428817"],"is_preprint":false},{"year":1999,"finding":"ECP-51 (RUVBL2) and ECP-54 (RUVBL1/TIP49) interact with each other as demonstrated by yeast two-hybrid, and both proteins localize to nucleus and cytoplasm.","method":"Yeast two-hybrid, affinity chromatography, subcellular fractionation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid interaction plus fractionation, single lab","pmids":["10524211"],"is_preprint":false},{"year":2000,"finding":"Reptin52 (RUVBL2) physically binds beta-catenin and TBP, and acts as an antagonistic regulator of beta-catenin/TCF-mediated transactivation, opposing the activating function of Pontin52 (RUVBL1). The antagonistic relationship is conserved in Drosophila Wingless signaling in vivo.","method":"Co-immunoprecipitation, reporter gene assays, Drosophila genetic epistasis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, reporter assays, and in vivo genetic validation across two organisms","pmids":["11080158"],"is_preprint":false},{"year":2001,"finding":"TIP49b (RUVBL2) interacts with ATF2 in a phosphorylation-dependent manner, requiring ATF2 residues 150-248, and attenuates ATF2 transcriptional activity under normal and stress (UV, ionizing radiation, p38 activation) conditions.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter gene assays, mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional reporter assays, multiple conditions tested in single lab","pmids":["11713276"],"is_preprint":false},{"year":2005,"finding":"Reptin (RUVBL2/Tip48) and Pontin (RUVBL1/Tip49) bind Myc in Drosophila and form complexes required for tissue growth; Pont shows dominant genetic interaction with dMyc affecting development, size, and target gene repression (e.g., mfas).","method":"Co-immunoprecipitation, Drosophila genetic interaction/epistasis, mitotic clones, reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo genetic epistasis, multiple orthogonal approaches","pmids":["16087886"],"is_preprint":false},{"year":2005,"finding":"TIP48 (RUVBL2) relocalizes during mitosis: in interphase it is predominantly nuclear with nuclear-periphery enrichment; upon mitosis it is excluded from condensing chromosomes, associates with the mitotic apparatus, and accumulates at the midzone/midbody during anaphase and cytokinesis. This relocalization is independent of microtubule assembly.","method":"Immunofluorescence microscopy, subcellular fractionation, cell cycle analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunofluorescence localization with functional context (mitosis), single lab","pmids":["16157330"],"is_preprint":false},{"year":2006,"finding":"Recombinant human TIP48 (RUVBL2) and TIP49 (RUVBL1) form a stable dodecameric complex (two stacked hexameric rings with C6 symmetry) with synergistic ATPase activity. Catalytic mutations in either subunit abolish ATPase activity of the entire complex. No helicase activity was detected for the purified complex in vitro.","method":"In vitro reconstitution, ATPase assays, site-directed mutagenesis, negative-stain electron microscopy, 3D reconstruction","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution, ATPase assays with mutagenesis, structural EM analysis, single lab with multiple orthogonal methods","pmids":["17157868"],"is_preprint":false},{"year":2008,"finding":"Yeast Rvb1 and Rvb2 form a heterohexameric ring (not a dodecamer) with enhanced ATPase activity stimulated by double-stranded DNA with overhangs, and exhibit 5'-to-3' DNA helicase activity in vitro.","method":"In vitro reconstitution, ATPase assays, DNA helicase assays, electron microscopy","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution plus enzymatic assays plus structural EM, single lab, multiple orthogonal methods","pmids":["18234224"],"is_preprint":false},{"year":2009,"finding":"RUVBL2 is identified as a novel AS160-binding protein. In 3T3-L1 adipocytes, RUVBL2 is highly expressed and cytosolic. Depletion of RUVBL2 inhibits insulin-stimulated GLUT4 translocation and glucose uptake by reducing insulin-stimulated AS160 phosphorylation; re-expression of RUVBL2 reverses this effect.","method":"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, GLUT4 translocation assay, glucose uptake assay","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS identification confirmed by Co-IP, functional knockdown/rescue, single lab","pmids":["19532121"],"is_preprint":false},{"year":2009,"finding":"TIP48 (RUVBL2) and TIP49 (RUVBL1) play a major role in H2A.Z exchange by catalyzing H2A acetylation-induced H2A.Z-H2B incorporation into nucleosomes via their ATPase activities, as part of small and big SRCAP/TIP60 complexes.","method":"Biochemical purification of complexes, in vitro histone exchange assays, ATPase mutants, ChIP","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro exchange assays, ATPase mutant analysis, complex purification, single lab with multiple orthogonal methods","pmids":["19696079"],"is_preprint":false},{"year":2010,"finding":"RUVBL1 and RUVBL2 physically associate with each member of the PIKK family and control PIKK mRNA abundance. They associate with SMG-1 and mRNPs in the cytoplasm and promote formation of mRNA surveillance complexes during nonsense-mediated mRNA decay (NMD).","method":"Co-immunoprecipitation, siRNA knockdown, immunoprecipitation of mRNPs, NMD functional assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional NMD assays, knockdown studies, multiple PIKKs tested, single lab","pmids":["20371770"],"is_preprint":false},{"year":2010,"finding":"Human TIP49b (RUVBL2) monomers cooperatively bind ssDNA and support 3'-to-5' DNA unwinding activity requiring a 3'-protruding tail ≥30 nt. Hexameric TIP49b is inactive for ATP hydrolysis and DNA unwinding, suggesting hexamerization is an inhibitory state.","method":"DNA binding assays, ATPase assays, helicase assays, sedimentation analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assays, multiple substrates tested, single lab","pmids":["20553504"],"is_preprint":false},{"year":2011,"finding":"The first crystal structure of the human RuvBL1-RuvBL2 complex (with truncated domain II) reveals a dodecamer of two heterohexameric rings with alternating RUVBL1 and RUVBL2 monomers bound to ADP/ATP, interacting via retained domain II. Truncation of domain II increases ATPase activity, and domain II auto-inhibits helicase activity.","method":"X-ray crystallography, SAXS, ATPase assays, helicase assays, mutagenesis","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SAXS confirmation plus enzymatic assays, multiple orthogonal methods","pmids":["21933716"],"is_preprint":false},{"year":2012,"finding":"Cryo-EM structures of human RuvBL1-RuvBL2 reveal two coexisting conformations (compact and stretched) driven by movements in DII domains. DII domains connect with the AAA+ core and bind nucleic acids; conformational transitions regulate exposure of DNA-binding regions.","method":"Cryo-electron microscopy, image classification, 3D reconstruction at ~15 Å","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural analysis, single lab, no functional mutagenesis validation in this paper","pmids":["23002137"],"is_preprint":false},{"year":2012,"finding":"Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses in vivo, as established by forward genetic screen with a point mutation in Ruvbl2 (Worker mutant mice).","method":"ENU chemical mutagenesis forward genetic screen, positional cloning, immunological phenotyping in mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function genetic screen with defined phenotype, single lab","pmids":["22761313"],"is_preprint":false},{"year":2012,"finding":"RUVBL2 binds to the distal region of the ARF promoter and represses ARF transcription. Ectopic expression of RUVBL2 decreases ARF levels, and knockdown increases ARF levels. RUVBL2 down-regulates p53 in an ARF-dependent manner.","method":"Chromatin immunoprecipitation (ChIP), overexpression/knockdown, luciferase reporter assay, western blotting","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus gain/loss-of-function with epistasis to ARF-p53, single lab","pmids":["22285491"],"is_preprint":false},{"year":2013,"finding":"Reptin/RUVBL2 directly interacts with the PCD protein Lrrc6/Seahorse in the cytosol. In reptin mutant zebrafish, axonemal dynein arm density is reduced despite unchanged dynein component mRNA levels, indicating Reptin-Lrrc6 complex is required for dynein arm assembly in cilia.","method":"Co-immunoprecipitation, zebrafish genetics (mutant analysis), immunofluorescence/colocalization, transmission electron microscopy of cilia","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, in vivo genetic loss-of-function, ultrastructural analysis, multiple orthogonal methods","pmids":["23858445"],"is_preprint":false},{"year":2013,"finding":"GATA3 associates with RUVBL2 and directly binds the Cdkn2c (p18) locus in an RUVBL2-dependent manner to repress Cdkn2c expression, thereby promoting Th2 cell proliferation. Knockdown of RUVBL2 impairs antigen-induced Th2 expansion and airway inflammation in vivo.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, in vivo mouse model of airway inflammation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, knockdown with defined molecular phenotype and in vivo validation, multiple methods","pmids":["24167278"],"is_preprint":false},{"year":2013,"finding":"TIP48/Reptin (RUVBL2) and H2A.Z are required for chromatin remodeling at the CCND1 locus prior to estrogen receptor binding. TIP48 promotes acetylation and exchange of H2A.Z, which triggers dissociation of a repressive intragenic CCND1 loop, enabling ERα binding at the promoter.","method":"ChIP, siRNA knockdown, 3C (chromosome conformation capture), H2A.Z exchange assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, 3C, siRNA with defined molecular readout of chromatin loop dissolution, single lab with multiple methods","pmids":["23637611"],"is_preprint":false},{"year":2013,"finding":"RUVBL2 is required for leukemogenic activity of MLL-AF9; its expression depends on MLL-AF9, and shRNA-mediated silencing impairs proliferation, survival, and telomerase activity of MLL-AF9 leukemia cells. A dominant-negative Walker B mutant of RUVBL2 confirmed the ATPase activity requirement.","method":"shRNA knockdown, dominant-negative ATPase mutant, telomerase assay, clonogenic assay, cell viability assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with ATPase mutant validation, multiple functional readouts, single lab","pmids":["23403462"],"is_preprint":false},{"year":2014,"finding":"RuvBL1-RuvBL2 AAA+ ATPases co-purify with the FA core complex under native conditions. Depletion of RuvBL1-RuvBL2 causes co-depletion of FA core complex proteins, DNA crosslinker hypersensitivity, chromosomal instability, and defective FA pathway activation in human cells. Conditional knockout of RuvBL1 in mouse HSCs causes aplastic anaemia.","method":"Affinity purification/mass spectrometry under native conditions, siRNA knockdown, conditional mouse KO, chromosomal fragility assays, western blotting","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — native co-purification, functional knockdown with multiple hallmark FA phenotypes, in vivo mouse KO, replicated across human and mouse models","pmids":["25428364"],"is_preprint":false},{"year":2014,"finding":"YY1 oligomers bind RuvBL1-RuvBL2 hetero-oligomeric complexes preferentially via RuvBL1. YY1 and the ATPase activity of RUVBL2 are required for RAD51 foci formation during homologous recombination.","method":"Electron microscopy, co-immunoprecipitation, bimolecular fluorescence complementation, ATPase mutant analysis, RAD51 foci immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, EM, ATPase mutant with functional HR readout, single lab","pmids":["24990942"],"is_preprint":false},{"year":2015,"finding":"RuvbL1 and RuvbL2 function as protein disaggregases: depletion suppresses aggresome formation and causes buildup of cytoplasmic aggregates. Synphilin-1 interacts directly with RuvbL1 near the opening of the central channel. Unfolded polypeptides and amyloid fibrils stimulate RuvbL ATPase activity, and RuvbL promotes disassembly of protein aggregates.","method":"siRNA screen, co-immunoprecipitation, aggresome formation assays, ATPase stimulation assays, protein disaggregation assays, yeast genetics","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical disaggregation assays, ATPase stimulation, co-IP, siRNA screen, corroborated in yeast; single lab with multiple orthogonal methods","pmids":["26303906"],"is_preprint":false},{"year":2017,"finding":"RUVBL1-RUVBL2 (R2TP/PFDL) interact with the U5 snRNP, with the interaction mediated primarily by ZNHIT2 binding to RUVBL2 via its zinc-finger HIT domain. Disruption of ZNHIT2 and RUVBL2 expression alters U5 snRNP protein composition, indicating a role in U5 snRNP assembly.","method":"Multiple target affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, proteomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — AP-MS, Co-IP, functional knockdown with complex composition readout, single lab with multiple orthogonal methods","pmids":["28561026"],"is_preprint":false},{"year":2017,"finding":"A domain in the Ino80 ATPase subunit (Ino80INS) stimulates Rvb1/Rvb2 ATPase activity 16-fold and promotes dodecamerization. Ino80INS binds asymmetrically along the dodecamerization interface, producing a conformationally flexible dodecamer that collapses to hexamers upon ATP addition, consistent with a protein assembly chaperone mechanism.","method":"ATPase assays, mass spectrometry cross-linking, cryo-EM, integrative structural modeling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, cryo-EM, cross-linking MS, biochemical ATPase assays, single lab with multiple orthogonal methods","pmids":["28591576"],"is_preprint":false},{"year":2017,"finding":"Liver-specific conditional knockout of Reptin/RUVBL2 in mice decreases mTOR protein abundance. Reptin maintains mTOR protein level through its ATPase activity (demonstrated in primary hepatocytes). Loss of Reptin differentially affects mTORC1 (inhibited) and mTORC2 (enhanced) signaling.","method":"Conditional knockout mouse model, primary hepatocyte experiments, ATPase inhibitor, western blotting, metabolic phenotyping","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO, ATPase-activity-dependent mechanism in primary cells, multiple signaling readouts, single lab","pmids":["29074727"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structures of human R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) reveal how PIH1D1 binding 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 ATPase activity.","method":"Cryo-electron microscopy, ATPase assays, mutagenesis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus biochemical ATPase validation, single lab with multiple orthogonal methods","pmids":["31049401"],"is_preprint":false},{"year":2019,"finding":"RUVBL1/2 ATPase activity is necessary for maturation/dissociation of the PAQosome. Inhibition of RUVBL1/2 ATPase activity causes S-phase arrest and replication catastrophe in cancer cells.","method":"Specific ATPase inhibitor treatment, PAQosome complex analysis, cell cycle analysis, cell viability assays","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor, complex composition analysis, cell cycle readout, single lab","pmids":["31883965"],"is_preprint":false},{"year":2019,"finding":"RUVBL2 is required for the oncogenic function of c-MYB in AML. Silencing RUVBL2 increases c-MYB binding at myeloid differentiation gene loci and activates their transcription, triggering AML cell apoptosis and impairing disease in engrafted mice.","method":"shRNA knockdown, ChIP-seq, RNA-seq, in vivo xenograft mouse model","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, RNA-seq, in vivo xenograft, functional loss-of-function, single lab with multiple orthogonal methods","pmids":["31138842"],"is_preprint":false},{"year":2020,"finding":"RUVBL1-RUVBL2 assembles and controls composition of the γ-tubulin ring complex (γTuRC) in human cells and in a heterologous coexpression system. RUVBL interacts with γTuRC subcomplexes but is absent from fully assembled γTuRC. Reconstituted γTuRC has microtubule nucleation activity and ~4 Å cryo-EM structure.","method":"Cryo-electron microscopy, heterologous coexpression reconstitution, co-immunoprecipitation, depletion in cells, microtubule nucleation assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution, functional nucleation assay, co-IP, validated in cells and recombinant system","pmids":["33355144"],"is_preprint":false},{"year":2020,"finding":"RUVBL2 interacts with BMAL1 and other clock proteins on chromatin at E-box loci to regulate circadian phase. Pharmacological perturbation with cordycepin (an adenosine analog) causes disassembly of the RUVBL2-BMAL1 interaction and the circadian super-complex, producing a phase shift. Crystal structure of RUVBL2 with cordycepin metabolite was solved.","method":"Crystal structure determination, spike-in ChIP-seq, co-immunoprecipitation, circadian bioluminescence assay, mouse pharmacology","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, ChIP-seq, Co-IP, functional circadian assay in cells and in vivo, multiple orthogonal methods","pmids":["32376767"],"is_preprint":false},{"year":2020,"finding":"Sorafenib is a mixed non-competitive inhibitor of RUVBL2 ATPase activity and also inhibits the RUVBL1/2 complex ATPase. The inhibitory effect is mediated by the insertion domain (DII) of RUVBL2, with no major effect on overall solution conformation.","method":"Enzyme kinetics, surface plasmon resonance, size-exclusion chromatography, SAXS","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme kinetics plus biophysical binding measurements, single lab","pmids":["32295120"],"is_preprint":false},{"year":2020,"finding":"DHX34, an RNA helicase involved in NMD initiation, directly interacts with RUVBL1-RUVBL2 in vitro and in cells. Cryo-EM shows DHX34 induces conformational changes in N-termini of every RUVBL2 subunit, stabilizing a nucleotide-free state and down-regulating ATP hydrolysis. DHX34 acts exclusively on RUVBL2 subunits (not RUVBL1).","method":"Cryo-electron microscopy, in vitro ATPase assays, co-immunoprecipitation, ATPase-deficient mutants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure, ATPase assays, mutagenesis distinguishing RUVBL1 vs RUVBL2 subunits, Co-IP, single lab with multiple orthogonal methods","pmids":["33205750"],"is_preprint":false},{"year":2021,"finding":"RUVBL2 (Reptin52) interacts with HIF-2α in both nuclear and cytoplasmic fractions, reduces HIF-2 transcriptional activity, and decreases EPO secretion under hypoxia by impairing HIF-2α stability via a non-canonical, PHD-VHL-proteasome-independent mechanism. ERK1/2 inactivation favors cytoplasmic association.","method":"Co-immunoprecipitation, reporter gene assay, pharmacological inhibitors, ELISA (EPO), western blotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assays, single lab","pmids":["33865222"],"is_preprint":false},{"year":2022,"finding":"RUVBL2 co-occupies promoters with RNA Pol II and various transcription factors, interacts with unphosphorylated RPB1 CTD in chromatin, and promotes RPB1 CTD clustering and transcription initiation. Rapid depletion of RUVBL2 decreases Pol II clusters and inhibits nascent RNA synthesis.","method":"ChIP-seq, rapid degron-mediated depletion (auxin-inducible degron), co-immunoprecipitation, super-resolution microscopy, nascent RNA sequencing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, rapid depletion, Co-IP, multiple cell lines and transcription factor contexts, multiple orthogonal methods","pmids":["36171202"],"is_preprint":false},{"year":2022,"finding":"RUVBL2 is required as a chaperone for tonicity-regulated nuclear export of NFAT5 under hypotonicity, where it cooperates with exportin-T (XPOT). RUVBL2 directly participates in the NFAT5 export machinery.","method":"siRNA screening, co-immunoprecipitation, proteomics, subcellular fractionation, fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen, Co-IP, localization studies, single lab with multiple methods","pmids":["35635291"],"is_preprint":false},{"year":2022,"finding":"Ruvbl2 functions as a suppressor of cardiomyocyte proliferation in zebrafish heart development and regeneration. Loss-of-function (deletion allele) causes ventricular hyperproliferation; myocardial overexpression is sufficient to suppress cardiomyocyte proliferation and rescue the hyperproliferative phenotype. This activity is cell-autonomous.","method":"ENU mutant analysis, CRISPR deletion allele generation, tissue-specific transgenic overexpression, EdU proliferation assay, cardiac regeneration model","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple alleles, rescue by overexpression, cell-autonomous demonstration; in vivo zebrafish genetics with multiple orthogonal approaches","pmids":["35178388"],"is_preprint":false},{"year":2024,"finding":"Rvb1 and Rvb2 arginine fingers have distinct active sites: replacing each arginine finger with different amino acids has different effects on ATPase activity, cell growth, and interactions with binding partners. Changes near the active site of Rvb1 or Rvb2 cause long-range effects on insertion domain dynamics, relaying active-site signals to cofactor binding sites; these arginine finger variants also impair snoRNP biogenesis.","method":"Site-directed mutagenesis, biochemical ATPase assays, yeast genetics, molecular dynamics simulations, snoRNP biogenesis assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis/ATPase assays plus MD simulations plus in vivo yeast genetics, preprint, single lab","pmids":["38798342"],"is_preprint":true},{"year":2025,"finding":"RUVBL2 is a conserved core component of the eukaryotic circadian clock across fungi, insects, and mammals. Wild-type RUVBL2 has an extremely slow intrinsic ATPase activity (~13 ATP/day). RUVBL2 variants identified by screening alter circadian period in mice (arrhythmic, short, long period). RUVBL2 orthologues physically interact with core clock proteins in humans, Drosophila, and Neurospora.","method":"AAV delivery of RUVBL2 variants to mouse SCN, enzymatic ATPase assays, co-immunoprecipitation across species, circadian locomotor assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo genetic variant screen, enzymatic assays, Co-IP across multiple species, replicated across organisms","pmids":["40140583"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of human RUVBL1-RUVBL2-CCDC103 complex (R2C) at 3.2 Å reveals a hetero-hexameric RUVBL1-RUVBL2 ring bound to three CCDC103 molecules via RUVBL2-binding domains. CCDC103's flexible N-terminal region regulates RUVBL1-RUVBL2 oligomerisation. This complex functions in HSP90-mediated assembly of axonemal dynein motors, relevant to Primary Ciliary Dyskinesia.","method":"Cryo-electron microscopy, biochemical reconstitution, structural analysis","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM structure (3.2 Å) with biochemical reconstitution, preprint, single lab","pmids":["bio_10.1101_2025.09.11.675549"],"is_preprint":true},{"year":2025,"finding":"RUVBL2 functions as a replication-specific cofactor for the influenza A virus polymerase, as distinguished from transcription-specific cofactors by differential interactome screening.","method":"Differential affinity purification/mass spectrometry interactome screen, functional siRNA knockdown with viral replication assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — AP-MS plus knockdown, preprint, single lab, viral context","pmids":["bio_10.1101_2025.06.06.658254"],"is_preprint":true}],"current_model":"RUVBL2 (Reptin52/TIP48) is a highly conserved AAA+ ATPase that forms a heterohexameric (and sometimes dodecameric) ring with RUVBL1, exhibiting ATPase and context-dependent DNA helicase activity regulated by its inserted DII domain; it functions as a versatile assembly chaperone and scaffold within multiple essential complexes—including R2TP, INO80, SWR-C, Tip60, and the FA core complex—to drive assembly of PIKKs, snoRNPs, RNA Pol II, γTuRC, and axonemal dynein motors, while also acting as a transcriptional co-regulator (antagonizing β-catenin/TCF, repressing ATF2, ARF, and HIF-2α, promoting Pol II CTD clustering, and controlling circadian clock phase and period via its unusually slow intrinsic ATPase activity), and additionally participates in protein disaggregation, GLUT4-mediated glucose uptake through AS160, NMD, and cilia motility through the Lrrc6 interaction."},"narrative":{"mechanistic_narrative":"RUVBL2 (Reptin52/TIP48/TIP49b) is a highly conserved AAA+ ATPase that partners with RUVBL1 to form heterohexameric rings and stacked dodecamers, serving as a versatile assembly chaperone and transcriptional co-regulator across many essential nuclear and cytoplasmic complexes [PMID:10428817, PMID:17157868, PMID:21933716]. The two proteins physically interact and co-purify in a large complex, and the assembled RUVBL1-RUVBL2 oligomer has synergistic ATPase activity that requires catalytically intact subunits, while in vitro DNA helicase activity is auto-inhibited by the inserted domain II (DII) [PMID:10428817, PMID:17157868, PMID:21933716]. DII is the principal regulatory hub: its truncation increases ATPase activity, conformational transitions between compact and stretched states control DNA-binding region exposure, and cofactor binding to DII or to the RUVBL2 N-terminal gatekeeper tunes nucleotide exchange and hydrolysis [PMID:21933716, PMID:23002137, PMID:31049401]. Cofactors act on the two subunits asymmetrically and often specifically on RUVBL2 — PIH1D1 of the R2TP complex destabilizes the RUVBL2 N-terminal gatekeeper, the Ino80 insertion domain drives dodecamerization and stimulates ATPase 16-fold, and the NMD helicase DHX34 stabilizes a nucleotide-free RUVBL2 state to down-regulate hydrolysis [PMID:28591576, PMID:31049401, PMID:33205750]. Through these regulated states RUVBL1-RUVBL2 assembles diverse machines: it incorporates H2A.Z into nucleosomes within SRCAP/TIP60 complexes and remodels chromatin at the CCND1 locus to license estrogen receptor binding, it associates with all PIKK-family kinases and SMG-1 mRNPs to promote NMD surveillance complexes, it assembles the U5 snRNP via ZNHIT2 binding to RUVBL2, it builds and controls the composition of the γ-tubulin ring complex for microtubule nucleation, and it co-purifies with the Fanconi anemia core complex to maintain crosslink repair and genome stability [PMID:19696079, PMID:23637611, PMID:20371770, PMID:28561026, PMID:33355144, PMID:25428364]. RUVBL2 also acts directly as a transcriptional co-regulator, antagonizing β-catenin/TCF and Myc, attenuating ATF2, repressing the ARF promoter to down-regulate p53, repressing HIF-2α activity, and promoting clustering of unphosphorylated RNA Pol II CTD to drive transcription initiation [PMID:11080158, PMID:16087886, PMID:11713276, PMID:22285491, PMID:33865222, PMID:36171202]. Beyond the nucleus it functions as a protein disaggregase whose ATPase is stimulated by unfolded polypeptides and amyloid fibrils, supports insulin-stimulated GLUT4 translocation through AS160, maintains mTOR protein levels, and assembles axonemal dynein motors via Lrrc6 and CCDC103 interactions, a function linked to ciliary dyskinesia [PMID:26303906, PMID:19532121, PMID:29074727, PMID:23858445, PMID:bio_10.1101_2025.09.11.675549]. RUVBL2 is a conserved core component of the eukaryotic circadian clock, interacting with BMAL1 and other clock proteins on E-box chromatin and setting circadian period through its unusually slow intrinsic ATPase activity (~13 ATP/day), with variants altering period in mice [PMID:32376767, PMID:40140583]. Loss- and gain-of-function studies establish in vivo roles in T-cell and Th2 development, leukemogenesis driven by MLL-AF9 and c-MYB, and suppression of cardiomyocyte proliferation [PMID:22761313, PMID:24167278, PMID:23403462, PMID:31138842, PMID:35178388].","teleology":[{"year":1999,"claim":"Established that RUVBL2 is an enzyme and an obligate partner of RUVBL1, defining the founding biochemical activities of the protein.","evidence":"In vitro ATPase and helicase assays plus co-purification and yeast two-hybrid showing TIP49b/RUVBL2 binds TIP49a/RUVBL1 in a ~700 kDa complex","pmids":["10428817","10524211"],"confidence":"High","gaps":["Helicase polarity and substrate requirements not yet reconciled with later complex-context findings","Cellular function not addressed"]},{"year":2000,"claim":"Showed RUVBL2 is not merely an enzyme but a transcriptional regulator that antagonizes its own partner RUVBL1 in Wnt signaling, revealing functional opposition within the heterodimer.","evidence":"Co-IP with beta-catenin and TBP, reporter assays, and Drosophila Wingless genetic epistasis","pmids":["11080158"],"confidence":"High","gaps":["Molecular basis of the antagonism between RUVBL1 and RUVBL2 not resolved","Does not connect transcriptional role to ATPase activity"]},{"year":2001,"claim":"Extended the transcriptional co-regulator role by showing phosphorylation-dependent, condition-specific repression of a stress-responsive factor.","evidence":"Yeast two-hybrid, co-IP, and reporter assays mapping ATF2 interaction and attenuation under UV/IR/p38 stress","pmids":["11713276"],"confidence":"High","gaps":["Whether repression requires the RUVBL1-RUVBL2 complex or chromatin remodeling unknown"]},{"year":2005,"claim":"Resolved the basic oligomeric architecture and showed the complex's ATPase is cooperative and helicase-silent in isolation, reframing RUVBL2 as a scaffold rather than a standalone helicase.","evidence":"Recombinant reconstitution, ATPase assays with catalytic mutants, and negative-stain EM showing a dodecamer; plus Myc-binding Drosophila genetics and mitotic relocalization imaging","pmids":["17157868","16087886","16157330"],"confidence":"High","gaps":["Reconciliation of dodecamer vs hexamer states with activity left open","Mechanism of helicase suppression in the complex unknown"]},{"year":2008,"claim":"Defined the DII insertion domain as the regulatory element controlling oligomerization-dependent ATPase and helicase activity, explaining the apparent contradictions in earlier enzymatic data.","evidence":"Yeast Rvb1/Rvb2 reconstitution and human monomer/hexamer enzymatic assays comparing active and inhibited states","pmids":["18234224","20553504"],"confidence":"Medium","gaps":["Species and oligomeric-state differences in helicase activity not fully resolved","Physiological relevance of monomeric activity unclear"]},{"year":2009,"claim":"Connected the ATPase to a defined chromatin function — ATP-dependent H2A.Z deposition — placing RUVBL2 mechanistically within SRCAP/TIP60 remodeling complexes.","evidence":"Complex purification, in vitro histone exchange assays with ATPase mutants, and ChIP; plus AS160-binding AP-MS and GLUT4 knockdown/rescue identifying a cytosolic metabolic role","pmids":["19696079","19532121"],"confidence":"High","gaps":["How the same ATPase serves both chromatin remodeling and cytosolic GLUT4 trafficking unexplained"]},{"year":2010,"claim":"Established RUVBL1-RUVBL2 as a PIKK assembly chaperone and showed direct involvement in cytoplasmic mRNA surveillance complexes for NMD.","evidence":"Reciprocal Co-IP across the PIKK family, mRNP IP, and functional NMD assays with knockdown","pmids":["20371770"],"confidence":"High","gaps":["Whether RUVBL2 stabilizes nascent PIKKs co-translationally not addressed"]},{"year":2011,"claim":"Provided the first atomic-resolution view, defining the dodecameric architecture and demonstrating that DII auto-inhibits both ATPase and helicase activity.","evidence":"X-ray crystallography of the DII-truncated complex with SAXS and enzymatic assays","pmids":["21933716"],"confidence":"High","gaps":["Full-length DII conformation not visualized in the crystal","Cofactor-bound regulatory states not captured"]},{"year":2012,"claim":"Revealed conformational dynamics of DII linking nucleotide state to DNA-binding region exposure, providing a structural basis for activity regulation, and broadened the functional repertoire to ARF/p53 repression and in vivo immune development.","evidence":"Cryo-EM conformational classification; ChIP and gain/loss-of-function at the ARF promoter; ENU forward-genetic Ruvbl2 mouse mutant with T-cell phenotyping","pmids":["23002137","22285491","22761313"],"confidence":"Medium","gaps":["Conformational states lacked functional mutagenesis validation in the structural paper","Direct vs indirect mode of ARF promoter repression unresolved"]},{"year":2013,"claim":"Integrated chromatin remodeling, ciliary motor assembly, and oncogenic transcription, demonstrating the breadth of RUVBL2-dependent assembly and regulatory activities in vivo.","evidence":"ChIP/3C at CCND1; zebrafish reptin-Lrrc6 genetics with cilia EM; GATA3/Cdkn2c ChIP and Th2 airway model; MLL-AF9 leukemia shRNA with ATPase-mutant rescue","pmids":["23637611","23858445","24167278","23403462"],"confidence":"High","gaps":["Common molecular principle linking these diverse functions not unified","Whether dynein arm assembly requires RUVBL2 ATPase not directly tested"]},{"year":2014,"claim":"Demonstrated direct roles in genome maintenance, coupling RUVBL2 ATPase to the Fanconi anemia pathway and homologous recombination.","evidence":"Native AP-MS with FA core complex, knockdown crosslinker-sensitivity and chromosomal fragility assays, conditional mouse KO; plus YY1/RUVBL EM and RAD51 foci with ATPase mutants","pmids":["25428364","24990942"],"confidence":"High","gaps":["Whether RUVBL2 chaperones FA core complex assembly or acts catalytically at lesions unclear"]},{"year":2015,"claim":"Identified a chaperone-independent cytoplasmic activity — protein disaggregation — with substrate-stimulated ATPase, expanding RUVBL2 beyond complex assembly.","evidence":"siRNA screen, aggresome and disaggregation assays, Synphilin-1 Co-IP near the central channel, ATPase stimulation by unfolded/amyloid substrates, yeast corroboration","pmids":["26303906"],"confidence":"High","gaps":["Whether disaggregation uses the same threading mechanism as classical disaggregases not established"]},{"year":2017,"claim":"Established subunit-specific cofactor regulation and the assembly-chaperone mechanism, showing distinct cofactors engage RUVBL2 versus RUVBL1 and toggle dodecamer-to-hexamer transitions.","evidence":"U5 snRNP AP-MS with ZNHIT2-RUVBL2 mapping; Ino80INS cryo-EM, crosslinking-MS, and 16-fold ATPase stimulation; liver-specific Reptin KO showing ATPase-dependent mTOR maintenance","pmids":["28561026","28591576","29074727"],"confidence":"High","gaps":["General rules governing which cofactors select RUVBL1 vs RUVBL2 not formalized"]},{"year":2019,"claim":"Defined how a dedicated R2TP cofactor regulates RUVBL2 nucleotide exchange and tied ATPase activity to PAQosome maturation and oncogenic transcription programs.","evidence":"R2TP cryo-EM showing PIH1D1-DII destabilizing the RUVBL2 N-terminal gatekeeper; ATPase-inhibitor-induced replication catastrophe; c-MYB AML ChIP-seq/RNA-seq with xenografts","pmids":["31049401","31883965","31138842"],"confidence":"High","gaps":["Therapeutic window for ATPase inhibition in cancer not defined within these studies"]},{"year":2020,"claim":"Revealed RUVBL2 as a core circadian clock component and a γTuRC assembly factor, and characterized small-molecule modulators acting through DII and RUVBL2 subunits.","evidence":"RUVBL2-BMAL1 ChIP-seq/Co-IP with cordycepin crystal structure and circadian assays; γTuRC cryo-EM, reconstitution, and nucleation assays; DHX34 cryo-EM stabilizing nucleotide-free RUVBL2; sorafenib enzyme kinetics on DII; NFAT5 nuclear export chaperone role","pmids":["32376767","33355144","33205750","32295120","35635291"],"confidence":"High","gaps":["How a slow ATPase encodes circadian timing not yet mechanistically explained at this stage","Generalizability of subunit-specific cofactor action across all complexes untested"]},{"year":2022,"claim":"Defined a direct role in transcription initiation through RNA Pol II CTD clustering and an in vivo role suppressing cardiomyocyte proliferation.","evidence":"ChIP-seq, auxin-inducible degron depletion, Co-IP with unphosphorylated RPB1 CTD, super-resolution imaging, and nascent RNA-seq; zebrafish CRISPR alleles and rescue in cardiac regeneration","pmids":["36171202","35178388"],"confidence":"High","gaps":["Whether CTD clustering depends on the assembly-chaperone cycle or a distinct activity unclear"]},{"year":2025,"claim":"Identified RUVBL2 as a deeply conserved clock core component whose extraordinarily slow intrinsic ATPase sets circadian period, and resolved a dynein-assembly complex relevant to ciliary disease.","evidence":"AAV delivery of RUVBL2 period-altering variants to mouse SCN, ATPase rate measurement (~13 ATP/day), cross-species Co-IP with clock proteins; R2C cryo-EM (RUVBL1-RUVBL2-CCDC103) at 3.2 Å (preprint)","pmids":["40140583","bio_10.1101_2025.09.11.675549"],"confidence":"High","gaps":["How ATPase turnover rate is read out as circadian period not mechanistically resolved","CCDC103-R2C structure is a preprint"]},{"year":null,"claim":"It remains unresolved what unifying principle dictates how a single RUVBL1-RUVBL2 ATPase is selectively recruited and catalytically tuned to assemble such mechanistically distinct machines, and how its slow nucleotide cycle is converted into timing, assembly, and disaggregation outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No general code for cofactor-directed subunit specificity established","Link between ATPase turnover rate and circadian period output not mechanistically defined","Influenza polymerase cofactor role rests on a single preprint AP-MS/knockdown study"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,6,12,24,38]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,11,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,15,34]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[22,24,29,39]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,8,16,22]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[18,30,34]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,15,34]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20,21]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,22,25]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[30,38]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[29,16,39]}],"complexes":["R2TP/PAQosome","SRCAP/TIP60 (H2A.Z exchange) complex","Fanconi anemia core complex","γ-tubulin ring complex (γTuRC) assembly intermediate"],"partners":["RUVBL1","PIH1D1","RPAP3","ZNHIT2","DHX34","BMAL1","CCDC103","LRRC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y230","full_name":"RuvB-like 2","aliases":["48 kDa TATA box-binding protein-interacting protein","48 kDa TBP-interacting protein","51 kDa erythrocyte cytosolic protein","ECP-51","INO80 complex subunit J","Repressing pontin 52","Reptin 52","TIP49b","TIP60-associated protein 54-beta","TAP54-beta"],"length_aa":463,"mass_kda":51.2,"function":"Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (5' to 3') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity (PubMed:10428817, 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 (PubMed:14966270). 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). May also inhibit the transcriptional activity of ATF2 (PubMed:11713276). Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway where it negatively regulates expression of ER stress response genes (PubMed:25652260). May play a role in regulating the composition of the U5 snRNP complex (PubMed:28561026)","subcellular_location":"Nucleus matrix; Nucleus, nucleoplasm; Cytoplasm; Membrane; Dynein axonemal particle","url":"https://www.uniprot.org/uniprotkb/Q9Y230/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RUVBL2","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000183207","cell_line_id":"CID001727","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":"POLR2E","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/CID001727","total_profiled":1310},"omim":[{"mim_id":"620390","title":"HEAT REPEAT-CONTAINING PROTEIN 1; HEATR1","url":"https://www.omim.org/entry/620390"},{"mim_id":"618887","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, DELTA; NFKBID","url":"https://www.omim.org/entry/618887"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":232.1}],"url":"https://www.proteinatlas.org/search/RUVBL2"},"hgnc":{"alias_symbol":["RVB2","TIP48","TIP49b","Reptin52","ECP51","TIH2","INO80J","Rvb2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y230","domains":[{"cath_id":"3.40.50.300","chopping":"21-98_294-361","consensus_level":"medium","plddt":89.1796,"start":21,"end":361},{"cath_id":"2.40.50.360","chopping":"132-237","consensus_level":"medium","plddt":83.5712,"start":132,"end":237},{"cath_id":"1.10.8.60","chopping":"363-447","consensus_level":"high","plddt":92.7669,"start":363,"end":447}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y230","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y230-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y230-F1-predicted_aligned_error_v6.png","plddt_mean":84.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RUVBL2","jax_strain_url":"https://www.jax.org/strain/search?query=RUVBL2"},"sequence":{"accession":"Q9Y230","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y230.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y230/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y230"}},"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":"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":"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":"21933716","id":"PMC_21933716","title":"Structural and functional insights into a dodecameric molecular machine - 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TIP49b and TIP49a physically interact and co-purify in the same ~700 kDa complex in cells.\",\n      \"method\": \"Enzyme assays (ATPase, helicase), co-immunoprecipitation, size-exclusion chromatography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro enzymatic assays plus co-purification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10428817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ECP-51 (RUVBL2) and ECP-54 (RUVBL1/TIP49) interact with each other as demonstrated by yeast two-hybrid, and both proteins localize to nucleus and cytoplasm.\",\n      \"method\": \"Yeast two-hybrid, affinity chromatography, subcellular fractionation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid interaction plus fractionation, single lab\",\n      \"pmids\": [\"10524211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Reptin52 (RUVBL2) physically binds beta-catenin and TBP, and acts as an antagonistic regulator of beta-catenin/TCF-mediated transactivation, opposing the activating function of Pontin52 (RUVBL1). The antagonistic relationship is conserved in Drosophila Wingless signaling in vivo.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, Drosophila genetic epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, reporter assays, and in vivo genetic validation across two organisms\",\n      \"pmids\": [\"11080158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIP49b (RUVBL2) interacts with ATF2 in a phosphorylation-dependent manner, requiring ATF2 residues 150-248, and attenuates ATF2 transcriptional activity under normal and stress (UV, ionizing radiation, p38 activation) conditions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter gene assays, mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional reporter assays, multiple conditions tested in single lab\",\n      \"pmids\": [\"11713276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Reptin (RUVBL2/Tip48) and Pontin (RUVBL1/Tip49) bind Myc in Drosophila and form complexes required for tissue growth; Pont shows dominant genetic interaction with dMyc affecting development, size, and target gene repression (e.g., mfas).\",\n      \"method\": \"Co-immunoprecipitation, Drosophila genetic interaction/epistasis, mitotic clones, reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo genetic epistasis, multiple orthogonal approaches\",\n      \"pmids\": [\"16087886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIP48 (RUVBL2) relocalizes during mitosis: in interphase it is predominantly nuclear with nuclear-periphery enrichment; upon mitosis it is excluded from condensing chromosomes, associates with the mitotic apparatus, and accumulates at the midzone/midbody during anaphase and cytokinesis. This relocalization is independent of microtubule assembly.\",\n      \"method\": \"Immunofluorescence microscopy, subcellular fractionation, cell cycle analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunofluorescence localization with functional context (mitosis), single lab\",\n      \"pmids\": [\"16157330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Recombinant human TIP48 (RUVBL2) and TIP49 (RUVBL1) form a stable dodecameric complex (two stacked hexameric rings with C6 symmetry) with synergistic ATPase activity. Catalytic mutations in either subunit abolish ATPase activity of the entire complex. No helicase activity was detected for the purified complex in vitro.\",\n      \"method\": \"In vitro reconstitution, ATPase assays, site-directed mutagenesis, negative-stain electron microscopy, 3D reconstruction\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution, ATPase assays with mutagenesis, structural EM analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17157868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Rvb1 and Rvb2 form a heterohexameric ring (not a dodecamer) with enhanced ATPase activity stimulated by double-stranded DNA with overhangs, and exhibit 5'-to-3' DNA helicase activity in vitro.\",\n      \"method\": \"In vitro reconstitution, ATPase assays, DNA helicase assays, electron microscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution plus enzymatic assays plus structural EM, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18234224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RUVBL2 is identified as a novel AS160-binding protein. In 3T3-L1 adipocytes, RUVBL2 is highly expressed and cytosolic. Depletion of RUVBL2 inhibits insulin-stimulated GLUT4 translocation and glucose uptake by reducing insulin-stimulated AS160 phosphorylation; re-expression of RUVBL2 reverses this effect.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, GLUT4 translocation assay, glucose uptake assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS identification confirmed by Co-IP, functional knockdown/rescue, single lab\",\n      \"pmids\": [\"19532121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TIP48 (RUVBL2) and TIP49 (RUVBL1) play a major role in H2A.Z exchange by catalyzing H2A acetylation-induced H2A.Z-H2B incorporation into nucleosomes via their ATPase activities, as part of small and big SRCAP/TIP60 complexes.\",\n      \"method\": \"Biochemical purification of complexes, in vitro histone exchange assays, ATPase mutants, ChIP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro exchange assays, ATPase mutant analysis, complex purification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19696079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RUVBL1 and RUVBL2 physically associate with each member of the PIKK family and control PIKK mRNA abundance. They associate with SMG-1 and mRNPs in the cytoplasm and promote formation of mRNA surveillance complexes during nonsense-mediated mRNA decay (NMD).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunoprecipitation of mRNPs, NMD functional assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional NMD assays, knockdown studies, multiple PIKKs tested, single lab\",\n      \"pmids\": [\"20371770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human TIP49b (RUVBL2) monomers cooperatively bind ssDNA and support 3'-to-5' DNA unwinding activity requiring a 3'-protruding tail ≥30 nt. Hexameric TIP49b is inactive for ATP hydrolysis and DNA unwinding, suggesting hexamerization is an inhibitory state.\",\n      \"method\": \"DNA binding assays, ATPase assays, helicase assays, sedimentation analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assays, multiple substrates tested, single lab\",\n      \"pmids\": [\"20553504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The first crystal structure of the human RuvBL1-RuvBL2 complex (with truncated domain II) reveals a dodecamer of two heterohexameric rings with alternating RUVBL1 and RUVBL2 monomers bound to ADP/ATP, interacting via retained domain II. Truncation of domain II increases ATPase activity, and domain II auto-inhibits helicase activity.\",\n      \"method\": \"X-ray crystallography, SAXS, ATPase assays, helicase assays, mutagenesis\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SAXS confirmation plus enzymatic assays, multiple orthogonal methods\",\n      \"pmids\": [\"21933716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cryo-EM structures of human RuvBL1-RuvBL2 reveal two coexisting conformations (compact and stretched) driven by movements in DII domains. DII domains connect with the AAA+ core and bind nucleic acids; conformational transitions regulate exposure of DNA-binding regions.\",\n      \"method\": \"Cryo-electron microscopy, image classification, 3D reconstruction at ~15 Å\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural analysis, single lab, no functional mutagenesis validation in this paper\",\n      \"pmids\": [\"23002137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses in vivo, as established by forward genetic screen with a point mutation in Ruvbl2 (Worker mutant mice).\",\n      \"method\": \"ENU chemical mutagenesis forward genetic screen, positional cloning, immunological phenotyping in mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function genetic screen with defined phenotype, single lab\",\n      \"pmids\": [\"22761313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RUVBL2 binds to the distal region of the ARF promoter and represses ARF transcription. Ectopic expression of RUVBL2 decreases ARF levels, and knockdown increases ARF levels. RUVBL2 down-regulates p53 in an ARF-dependent manner.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), overexpression/knockdown, luciferase reporter assay, western blotting\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus gain/loss-of-function with epistasis to ARF-p53, single lab\",\n      \"pmids\": [\"22285491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Reptin/RUVBL2 directly interacts with the PCD protein Lrrc6/Seahorse in the cytosol. In reptin mutant zebrafish, axonemal dynein arm density is reduced despite unchanged dynein component mRNA levels, indicating Reptin-Lrrc6 complex is required for dynein arm assembly in cilia.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish genetics (mutant analysis), immunofluorescence/colocalization, transmission electron microscopy of cilia\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, in vivo genetic loss-of-function, ultrastructural analysis, multiple orthogonal methods\",\n      \"pmids\": [\"23858445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GATA3 associates with RUVBL2 and directly binds the Cdkn2c (p18) locus in an RUVBL2-dependent manner to repress Cdkn2c expression, thereby promoting Th2 cell proliferation. Knockdown of RUVBL2 impairs antigen-induced Th2 expansion and airway inflammation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, in vivo mouse model of airway inflammation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, knockdown with defined molecular phenotype and in vivo validation, multiple methods\",\n      \"pmids\": [\"24167278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIP48/Reptin (RUVBL2) and H2A.Z are required for chromatin remodeling at the CCND1 locus prior to estrogen receptor binding. TIP48 promotes acetylation and exchange of H2A.Z, which triggers dissociation of a repressive intragenic CCND1 loop, enabling ERα binding at the promoter.\",\n      \"method\": \"ChIP, siRNA knockdown, 3C (chromosome conformation capture), H2A.Z exchange assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, 3C, siRNA with defined molecular readout of chromatin loop dissolution, single lab with multiple methods\",\n      \"pmids\": [\"23637611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RUVBL2 is required for leukemogenic activity of MLL-AF9; its expression depends on MLL-AF9, and shRNA-mediated silencing impairs proliferation, survival, and telomerase activity of MLL-AF9 leukemia cells. A dominant-negative Walker B mutant of RUVBL2 confirmed the ATPase activity requirement.\",\n      \"method\": \"shRNA knockdown, dominant-negative ATPase mutant, telomerase assay, clonogenic assay, cell viability assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with ATPase mutant validation, multiple functional readouts, single lab\",\n      \"pmids\": [\"23403462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RuvBL1-RuvBL2 AAA+ ATPases co-purify with the FA core complex under native conditions. Depletion of RuvBL1-RuvBL2 causes co-depletion of FA core complex proteins, DNA crosslinker hypersensitivity, chromosomal instability, and defective FA pathway activation in human cells. Conditional knockout of RuvBL1 in mouse HSCs causes aplastic anaemia.\",\n      \"method\": \"Affinity purification/mass spectrometry under native conditions, siRNA knockdown, conditional mouse KO, chromosomal fragility assays, western blotting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — native co-purification, functional knockdown with multiple hallmark FA phenotypes, in vivo mouse KO, replicated across human and mouse models\",\n      \"pmids\": [\"25428364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 oligomers bind RuvBL1-RuvBL2 hetero-oligomeric complexes preferentially via RuvBL1. YY1 and the ATPase activity of RUVBL2 are required for RAD51 foci formation during homologous recombination.\",\n      \"method\": \"Electron microscopy, co-immunoprecipitation, bimolecular fluorescence complementation, ATPase mutant analysis, RAD51 foci immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, EM, ATPase mutant with functional HR readout, single lab\",\n      \"pmids\": [\"24990942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RuvbL1 and RuvbL2 function as protein disaggregases: depletion suppresses aggresome formation and causes buildup of cytoplasmic aggregates. Synphilin-1 interacts directly with RuvbL1 near the opening of the central channel. Unfolded polypeptides and amyloid fibrils stimulate RuvbL ATPase activity, and RuvbL promotes disassembly of protein aggregates.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, aggresome formation assays, ATPase stimulation assays, protein disaggregation assays, yeast genetics\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical disaggregation assays, ATPase stimulation, co-IP, siRNA screen, corroborated in yeast; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26303906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RUVBL1-RUVBL2 (R2TP/PFDL) interact with the U5 snRNP, with the interaction mediated primarily by ZNHIT2 binding to RUVBL2 via its zinc-finger HIT domain. Disruption of ZNHIT2 and RUVBL2 expression alters U5 snRNP protein composition, indicating a role in U5 snRNP assembly.\",\n      \"method\": \"Multiple target affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS, Co-IP, functional knockdown with complex composition readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28561026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A domain in the Ino80 ATPase subunit (Ino80INS) stimulates Rvb1/Rvb2 ATPase activity 16-fold and promotes dodecamerization. Ino80INS binds asymmetrically along the dodecamerization interface, producing a conformationally flexible dodecamer that collapses to hexamers upon ATP addition, consistent with a protein assembly chaperone mechanism.\",\n      \"method\": \"ATPase assays, mass spectrometry cross-linking, cryo-EM, integrative structural modeling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, cryo-EM, cross-linking MS, biochemical ATPase assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28591576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Liver-specific conditional knockout of Reptin/RUVBL2 in mice decreases mTOR protein abundance. Reptin maintains mTOR protein level through its ATPase activity (demonstrated in primary hepatocytes). Loss of Reptin differentially affects mTORC1 (inhibited) and mTORC2 (enhanced) signaling.\",\n      \"method\": \"Conditional knockout mouse model, primary hepatocyte experiments, ATPase inhibitor, western blotting, metabolic phenotyping\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO, ATPase-activity-dependent mechanism in primary cells, multiple signaling readouts, single lab\",\n      \"pmids\": [\"29074727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structures of human R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) reveal how PIH1D1 binding 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 ATPase activity.\",\n      \"method\": \"Cryo-electron microscopy, ATPase assays, mutagenesis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus biochemical ATPase validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31049401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RUVBL1/2 ATPase activity is necessary for maturation/dissociation of the PAQosome. Inhibition of RUVBL1/2 ATPase activity causes S-phase arrest and replication catastrophe in cancer cells.\",\n      \"method\": \"Specific ATPase inhibitor treatment, PAQosome complex analysis, cell cycle analysis, cell viability assays\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor, complex composition analysis, cell cycle readout, single lab\",\n      \"pmids\": [\"31883965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RUVBL2 is required for the oncogenic function of c-MYB in AML. Silencing RUVBL2 increases c-MYB binding at myeloid differentiation gene loci and activates their transcription, triggering AML cell apoptosis and impairing disease in engrafted mice.\",\n      \"method\": \"shRNA knockdown, ChIP-seq, RNA-seq, in vivo xenograft mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, RNA-seq, in vivo xenograft, functional loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31138842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RUVBL1-RUVBL2 assembles and controls composition of the γ-tubulin ring complex (γTuRC) in human cells and in a heterologous coexpression system. RUVBL interacts with γTuRC subcomplexes but is absent from fully assembled γTuRC. Reconstituted γTuRC has microtubule nucleation activity and ~4 Å cryo-EM structure.\",\n      \"method\": \"Cryo-electron microscopy, heterologous coexpression reconstitution, co-immunoprecipitation, depletion in cells, microtubule nucleation assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution, functional nucleation assay, co-IP, validated in cells and recombinant system\",\n      \"pmids\": [\"33355144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RUVBL2 interacts with BMAL1 and other clock proteins on chromatin at E-box loci to regulate circadian phase. Pharmacological perturbation with cordycepin (an adenosine analog) causes disassembly of the RUVBL2-BMAL1 interaction and the circadian super-complex, producing a phase shift. Crystal structure of RUVBL2 with cordycepin metabolite was solved.\",\n      \"method\": \"Crystal structure determination, spike-in ChIP-seq, co-immunoprecipitation, circadian bioluminescence assay, mouse pharmacology\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, ChIP-seq, Co-IP, functional circadian assay in cells and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"32376767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sorafenib is a mixed non-competitive inhibitor of RUVBL2 ATPase activity and also inhibits the RUVBL1/2 complex ATPase. The inhibitory effect is mediated by the insertion domain (DII) of RUVBL2, with no major effect on overall solution conformation.\",\n      \"method\": \"Enzyme kinetics, surface plasmon resonance, size-exclusion chromatography, SAXS\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme kinetics plus biophysical binding measurements, single lab\",\n      \"pmids\": [\"32295120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DHX34, an RNA helicase involved in NMD initiation, directly interacts with RUVBL1-RUVBL2 in vitro and in cells. Cryo-EM shows DHX34 induces conformational changes in N-termini of every RUVBL2 subunit, stabilizing a nucleotide-free state and down-regulating ATP hydrolysis. DHX34 acts exclusively on RUVBL2 subunits (not RUVBL1).\",\n      \"method\": \"Cryo-electron microscopy, in vitro ATPase assays, co-immunoprecipitation, ATPase-deficient mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure, ATPase assays, mutagenesis distinguishing RUVBL1 vs RUVBL2 subunits, Co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33205750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RUVBL2 (Reptin52) interacts with HIF-2α in both nuclear and cytoplasmic fractions, reduces HIF-2 transcriptional activity, and decreases EPO secretion under hypoxia by impairing HIF-2α stability via a non-canonical, PHD-VHL-proteasome-independent mechanism. ERK1/2 inactivation favors cytoplasmic association.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, pharmacological inhibitors, ELISA (EPO), western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assays, single lab\",\n      \"pmids\": [\"33865222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUVBL2 co-occupies promoters with RNA Pol II and various transcription factors, interacts with unphosphorylated RPB1 CTD in chromatin, and promotes RPB1 CTD clustering and transcription initiation. Rapid depletion of RUVBL2 decreases Pol II clusters and inhibits nascent RNA synthesis.\",\n      \"method\": \"ChIP-seq, rapid degron-mediated depletion (auxin-inducible degron), co-immunoprecipitation, super-resolution microscopy, nascent RNA sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, rapid depletion, Co-IP, multiple cell lines and transcription factor contexts, multiple orthogonal methods\",\n      \"pmids\": [\"36171202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUVBL2 is required as a chaperone for tonicity-regulated nuclear export of NFAT5 under hypotonicity, where it cooperates with exportin-T (XPOT). RUVBL2 directly participates in the NFAT5 export machinery.\",\n      \"method\": \"siRNA screening, co-immunoprecipitation, proteomics, subcellular fractionation, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen, Co-IP, localization studies, single lab with multiple methods\",\n      \"pmids\": [\"35635291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ruvbl2 functions as a suppressor of cardiomyocyte proliferation in zebrafish heart development and regeneration. Loss-of-function (deletion allele) causes ventricular hyperproliferation; myocardial overexpression is sufficient to suppress cardiomyocyte proliferation and rescue the hyperproliferative phenotype. This activity is cell-autonomous.\",\n      \"method\": \"ENU mutant analysis, CRISPR deletion allele generation, tissue-specific transgenic overexpression, EdU proliferation assay, cardiac regeneration model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple alleles, rescue by overexpression, cell-autonomous demonstration; in vivo zebrafish genetics with multiple orthogonal approaches\",\n      \"pmids\": [\"35178388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rvb1 and Rvb2 arginine fingers have distinct active sites: replacing each arginine finger with different amino acids has different effects on ATPase activity, cell growth, and interactions with binding partners. Changes near the active site of Rvb1 or Rvb2 cause long-range effects on insertion domain dynamics, relaying active-site signals to cofactor binding sites; these arginine finger variants also impair snoRNP biogenesis.\",\n      \"method\": \"Site-directed mutagenesis, biochemical ATPase assays, yeast genetics, molecular dynamics simulations, snoRNP biogenesis assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis/ATPase assays plus MD simulations plus in vivo yeast genetics, preprint, single lab\",\n      \"pmids\": [\"38798342\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RUVBL2 is a conserved core component of the eukaryotic circadian clock across fungi, insects, and mammals. Wild-type RUVBL2 has an extremely slow intrinsic ATPase activity (~13 ATP/day). RUVBL2 variants identified by screening alter circadian period in mice (arrhythmic, short, long period). RUVBL2 orthologues physically interact with core clock proteins in humans, Drosophila, and Neurospora.\",\n      \"method\": \"AAV delivery of RUVBL2 variants to mouse SCN, enzymatic ATPase assays, co-immunoprecipitation across species, circadian locomotor assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo genetic variant screen, enzymatic assays, Co-IP across multiple species, replicated across organisms\",\n      \"pmids\": [\"40140583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of human RUVBL1-RUVBL2-CCDC103 complex (R2C) at 3.2 Å reveals a hetero-hexameric RUVBL1-RUVBL2 ring bound to three CCDC103 molecules via RUVBL2-binding domains. CCDC103's flexible N-terminal region regulates RUVBL1-RUVBL2 oligomerisation. This complex functions in HSP90-mediated assembly of axonemal dynein motors, relevant to Primary Ciliary Dyskinesia.\",\n      \"method\": \"Cryo-electron microscopy, biochemical reconstitution, structural analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM structure (3.2 Å) with biochemical reconstitution, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.11.675549\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RUVBL2 functions as a replication-specific cofactor for the influenza A virus polymerase, as distinguished from transcription-specific cofactors by differential interactome screening.\",\n      \"method\": \"Differential affinity purification/mass spectrometry interactome screen, functional siRNA knockdown with viral replication assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — AP-MS plus knockdown, preprint, single lab, viral context\",\n      \"pmids\": [\"bio_10.1101_2025.06.06.658254\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RUVBL2 (Reptin52/TIP48) is a highly conserved AAA+ ATPase that forms a heterohexameric (and sometimes dodecameric) ring with RUVBL1, exhibiting ATPase and context-dependent DNA helicase activity regulated by its inserted DII domain; it functions as a versatile assembly chaperone and scaffold within multiple essential complexes—including R2TP, INO80, SWR-C, Tip60, and the FA core complex—to drive assembly of PIKKs, snoRNPs, RNA Pol II, γTuRC, and axonemal dynein motors, while also acting as a transcriptional co-regulator (antagonizing β-catenin/TCF, repressing ATF2, ARF, and HIF-2α, promoting Pol II CTD clustering, and controlling circadian clock phase and period via its unusually slow intrinsic ATPase activity), and additionally participates in protein disaggregation, GLUT4-mediated glucose uptake through AS160, NMD, and cilia motility through the Lrrc6 interaction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RUVBL2 (Reptin52/TIP48/TIP49b) is a highly conserved AAA+ ATPase that partners with RUVBL1 to form heterohexameric rings and stacked dodecamers, serving as a versatile assembly chaperone and transcriptional co-regulator across many essential nuclear and cytoplasmic complexes [#0, #6, #12]. The two proteins physically interact and co-purify in a large complex, and the assembled RUVBL1-RUVBL2 oligomer has synergistic ATPase activity that requires catalytically intact subunits, while in vitro DNA helicase activity is auto-inhibited by the inserted domain II (DII) [#0, #6, #12]. DII is the principal regulatory hub: its truncation increases ATPase activity, conformational transitions between compact and stretched states control DNA-binding region exposure, and cofactor binding to DII or to the RUVBL2 N-terminal gatekeeper tunes nucleotide exchange and hydrolysis [#12, #13, #26]. Cofactors act on the two subunits asymmetrically and often specifically on RUVBL2 — PIH1D1 of the R2TP complex destabilizes the RUVBL2 N-terminal gatekeeper, the Ino80 insertion domain drives dodecamerization and stimulates ATPase 16-fold, and the NMD helicase DHX34 stabilizes a nucleotide-free RUVBL2 state to down-regulate hydrolysis [#24, #26, #32]. Through these regulated states RUVBL1-RUVBL2 assembles diverse machines: it incorporates H2A.Z into nucleosomes within SRCAP/TIP60 complexes and remodels chromatin at the CCND1 locus to license estrogen receptor binding, it associates with all PIKK-family kinases and SMG-1 mRNPs to promote NMD surveillance complexes, it assembles the U5 snRNP via ZNHIT2 binding to RUVBL2, it builds and controls the composition of the γ-tubulin ring complex for microtubule nucleation, and it co-purifies with the Fanconi anemia core complex to maintain crosslink repair and genome stability [#9, #18, #10, #23, #29, #20]. RUVBL2 also acts directly as a transcriptional co-regulator, antagonizing β-catenin/TCF and Myc, attenuating ATF2, repressing the ARF promoter to down-regulate p53, repressing HIF-2α activity, and promoting clustering of unphosphorylated RNA Pol II CTD to drive transcription initiation [#2, #4, #3, #15, #33, #34]. Beyond the nucleus it functions as a protein disaggregase whose ATPase is stimulated by unfolded polypeptides and amyloid fibrils, supports insulin-stimulated GLUT4 translocation through AS160, maintains mTOR protein levels, and assembles axonemal dynein motors via Lrrc6 and CCDC103 interactions, a function linked to ciliary dyskinesia [#22, #8, #25, #16, #39]. RUVBL2 is a conserved core component of the eukaryotic circadian clock, interacting with BMAL1 and other clock proteins on E-box chromatin and setting circadian period through its unusually slow intrinsic ATPase activity (~13 ATP/day), with variants altering period in mice [#30, #38]. Loss- and gain-of-function studies establish in vivo roles in T-cell and Th2 development, leukemogenesis driven by MLL-AF9 and c-MYB, and suppression of cardiomyocyte proliferation [#14, #17, #19, #28, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that RUVBL2 is an enzyme and an obligate partner of RUVBL1, defining the founding biochemical activities of the protein.\",\n      \"evidence\": \"In vitro ATPase and helicase assays plus co-purification and yeast two-hybrid showing TIP49b/RUVBL2 binds TIP49a/RUVBL1 in a ~700 kDa complex\",\n      \"pmids\": [\"10428817\", \"10524211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Helicase polarity and substrate requirements not yet reconciled with later complex-context findings\", \"Cellular function not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed RUVBL2 is not merely an enzyme but a transcriptional regulator that antagonizes its own partner RUVBL1 in Wnt signaling, revealing functional opposition within the heterodimer.\",\n      \"evidence\": \"Co-IP with beta-catenin and TBP, reporter assays, and Drosophila Wingless genetic epistasis\",\n      \"pmids\": [\"11080158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the antagonism between RUVBL1 and RUVBL2 not resolved\", \"Does not connect transcriptional role to ATPase activity\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extended the transcriptional co-regulator role by showing phosphorylation-dependent, condition-specific repression of a stress-responsive factor.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and reporter assays mapping ATF2 interaction and attenuation under UV/IR/p38 stress\",\n      \"pmids\": [\"11713276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether repression requires the RUVBL1-RUVBL2 complex or chromatin remodeling unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the basic oligomeric architecture and showed the complex's ATPase is cooperative and helicase-silent in isolation, reframing RUVBL2 as a scaffold rather than a standalone helicase.\",\n      \"evidence\": \"Recombinant reconstitution, ATPase assays with catalytic mutants, and negative-stain EM showing a dodecamer; plus Myc-binding Drosophila genetics and mitotic relocalization imaging\",\n      \"pmids\": [\"17157868\", \"16087886\", \"16157330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of dodecamer vs hexamer states with activity left open\", \"Mechanism of helicase suppression in the complex unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the DII insertion domain as the regulatory element controlling oligomerization-dependent ATPase and helicase activity, explaining the apparent contradictions in earlier enzymatic data.\",\n      \"evidence\": \"Yeast Rvb1/Rvb2 reconstitution and human monomer/hexamer enzymatic assays comparing active and inhibited states\",\n      \"pmids\": [\"18234224\", \"20553504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Species and oligomeric-state differences in helicase activity not fully resolved\", \"Physiological relevance of monomeric activity unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the ATPase to a defined chromatin function — ATP-dependent H2A.Z deposition — placing RUVBL2 mechanistically within SRCAP/TIP60 remodeling complexes.\",\n      \"evidence\": \"Complex purification, in vitro histone exchange assays with ATPase mutants, and ChIP; plus AS160-binding AP-MS and GLUT4 knockdown/rescue identifying a cytosolic metabolic role\",\n      \"pmids\": [\"19696079\", \"19532121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same ATPase serves both chromatin remodeling and cytosolic GLUT4 trafficking unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established RUVBL1-RUVBL2 as a PIKK assembly chaperone and showed direct involvement in cytoplasmic mRNA surveillance complexes for NMD.\",\n      \"evidence\": \"Reciprocal Co-IP across the PIKK family, mRNP IP, and functional NMD assays with knockdown\",\n      \"pmids\": [\"20371770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RUVBL2 stabilizes nascent PIKKs co-translationally not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the first atomic-resolution view, defining the dodecameric architecture and demonstrating that DII auto-inhibits both ATPase and helicase activity.\",\n      \"evidence\": \"X-ray crystallography of the DII-truncated complex with SAXS and enzymatic assays\",\n      \"pmids\": [\"21933716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length DII conformation not visualized in the crystal\", \"Cofactor-bound regulatory states not captured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed conformational dynamics of DII linking nucleotide state to DNA-binding region exposure, providing a structural basis for activity regulation, and broadened the functional repertoire to ARF/p53 repression and in vivo immune development.\",\n      \"evidence\": \"Cryo-EM conformational classification; ChIP and gain/loss-of-function at the ARF promoter; ENU forward-genetic Ruvbl2 mouse mutant with T-cell phenotyping\",\n      \"pmids\": [\"23002137\", \"22285491\", \"22761313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational states lacked functional mutagenesis validation in the structural paper\", \"Direct vs indirect mode of ARF promoter repression unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Integrated chromatin remodeling, ciliary motor assembly, and oncogenic transcription, demonstrating the breadth of RUVBL2-dependent assembly and regulatory activities in vivo.\",\n      \"evidence\": \"ChIP/3C at CCND1; zebrafish reptin-Lrrc6 genetics with cilia EM; GATA3/Cdkn2c ChIP and Th2 airway model; MLL-AF9 leukemia shRNA with ATPase-mutant rescue\",\n      \"pmids\": [\"23637611\", \"23858445\", \"24167278\", \"23403462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Common molecular principle linking these diverse functions not unified\", \"Whether dynein arm assembly requires RUVBL2 ATPase not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated direct roles in genome maintenance, coupling RUVBL2 ATPase to the Fanconi anemia pathway and homologous recombination.\",\n      \"evidence\": \"Native AP-MS with FA core complex, knockdown crosslinker-sensitivity and chromosomal fragility assays, conditional mouse KO; plus YY1/RUVBL EM and RAD51 foci with ATPase mutants\",\n      \"pmids\": [\"25428364\", \"24990942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RUVBL2 chaperones FA core complex assembly or acts catalytically at lesions unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a chaperone-independent cytoplasmic activity — protein disaggregation — with substrate-stimulated ATPase, expanding RUVBL2 beyond complex assembly.\",\n      \"evidence\": \"siRNA screen, aggresome and disaggregation assays, Synphilin-1 Co-IP near the central channel, ATPase stimulation by unfolded/amyloid substrates, yeast corroboration\",\n      \"pmids\": [\"26303906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether disaggregation uses the same threading mechanism as classical disaggregases not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established subunit-specific cofactor regulation and the assembly-chaperone mechanism, showing distinct cofactors engage RUVBL2 versus RUVBL1 and toggle dodecamer-to-hexamer transitions.\",\n      \"evidence\": \"U5 snRNP AP-MS with ZNHIT2-RUVBL2 mapping; Ino80INS cryo-EM, crosslinking-MS, and 16-fold ATPase stimulation; liver-specific Reptin KO showing ATPase-dependent mTOR maintenance\",\n      \"pmids\": [\"28561026\", \"28591576\", \"29074727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"General rules governing which cofactors select RUVBL1 vs RUVBL2 not formalized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how a dedicated R2TP cofactor regulates RUVBL2 nucleotide exchange and tied ATPase activity to PAQosome maturation and oncogenic transcription programs.\",\n      \"evidence\": \"R2TP cryo-EM showing PIH1D1-DII destabilizing the RUVBL2 N-terminal gatekeeper; ATPase-inhibitor-induced replication catastrophe; c-MYB AML ChIP-seq/RNA-seq with xenografts\",\n      \"pmids\": [\"31049401\", \"31883965\", \"31138842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window for ATPase inhibition in cancer not defined within these studies\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed RUVBL2 as a core circadian clock component and a γTuRC assembly factor, and characterized small-molecule modulators acting through DII and RUVBL2 subunits.\",\n      \"evidence\": \"RUVBL2-BMAL1 ChIP-seq/Co-IP with cordycepin crystal structure and circadian assays; γTuRC cryo-EM, reconstitution, and nucleation assays; DHX34 cryo-EM stabilizing nucleotide-free RUVBL2; sorafenib enzyme kinetics on DII; NFAT5 nuclear export chaperone role\",\n      \"pmids\": [\"32376767\", \"33355144\", \"33205750\", \"32295120\", \"35635291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a slow ATPase encodes circadian timing not yet mechanistically explained at this stage\", \"Generalizability of subunit-specific cofactor action across all complexes untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a direct role in transcription initiation through RNA Pol II CTD clustering and an in vivo role suppressing cardiomyocyte proliferation.\",\n      \"evidence\": \"ChIP-seq, auxin-inducible degron depletion, Co-IP with unphosphorylated RPB1 CTD, super-resolution imaging, and nascent RNA-seq; zebrafish CRISPR alleles and rescue in cardiac regeneration\",\n      \"pmids\": [\"36171202\", \"35178388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CTD clustering depends on the assembly-chaperone cycle or a distinct activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RUVBL2 as a deeply conserved clock core component whose extraordinarily slow intrinsic ATPase sets circadian period, and resolved a dynein-assembly complex relevant to ciliary disease.\",\n      \"evidence\": \"AAV delivery of RUVBL2 period-altering variants to mouse SCN, ATPase rate measurement (~13 ATP/day), cross-species Co-IP with clock proteins; R2C cryo-EM (RUVBL1-RUVBL2-CCDC103) at 3.2 Å (preprint)\",\n      \"pmids\": [\"40140583\", \"bio_10.1101_2025.09.11.675549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATPase turnover rate is read out as circadian period not mechanistically resolved\", \"CCDC103-R2C structure is a preprint\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what unifying principle dictates how a single RUVBL1-RUVBL2 ATPase is selectively recruited and catalytically tuned to assemble such mechanistically distinct machines, and how its slow nucleotide cycle is converted into timing, assembly, and disaggregation outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No general code for cofactor-directed subunit specificity established\", \"Link between ATPase turnover rate and circadian period output not mechanistically defined\", \"Influenza polymerase cofactor role rests on a single preprint AP-MS/knockdown study\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 6, 12, 24, 38]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 15, 34]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [22, 24, 29, 39]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 8, 16, 22]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [18, 30, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 15, 34]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 22, 25]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [30, 38]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [29, 16, 39]}\n    ],\n    \"complexes\": [\"R2TP/PAQosome\", \"SRCAP/TIP60 (H2A.Z exchange) complex\", \"Fanconi anemia core complex\", \"γ-tubulin ring complex (γTuRC) assembly intermediate\"],\n    \"partners\": [\"RUVBL1\", \"PIH1D1\", \"RPAP3\", \"ZNHIT2\", \"DHX34\", \"BMAL1\", \"CCDC103\", \"LRRC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}