Affinage

RUVBL2

RuvB-like 2 · UniProt Q9Y230

Length
463 aa
Mass
51.2 kDa
Annotated
2026-06-10
73 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    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

    PMID:10428817 PMID:10524211

    Open questions at the time
    • Helicase polarity and substrate requirements not yet reconciled with later complex-context findings
    • Cellular function not addressed
  2. 2000 High

    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

    PMID:11080158

    Open questions at the time
    • Molecular basis of the antagonism between RUVBL1 and RUVBL2 not resolved
    • Does not connect transcriptional role to ATPase activity
  3. 2001 High

    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

    PMID:11713276

    Open questions at the time
    • Whether repression requires the RUVBL1-RUVBL2 complex or chromatin remodeling unknown
  4. 2005 High

    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

    PMID:16087886 PMID:16157330 PMID:17157868

    Open questions at the time
    • Reconciliation of dodecamer vs hexamer states with activity left open
    • Mechanism of helicase suppression in the complex unknown
  5. 2008 Medium

    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

    PMID:18234224 PMID:20553504

    Open questions at the time
    • Species and oligomeric-state differences in helicase activity not fully resolved
    • Physiological relevance of monomeric activity unclear
  6. 2009 High

    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

    PMID:19532121 PMID:19696079

    Open questions at the time
    • How the same ATPase serves both chromatin remodeling and cytosolic GLUT4 trafficking unexplained
  7. 2010 High

    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

    PMID:20371770

    Open questions at the time
    • Whether RUVBL2 stabilizes nascent PIKKs co-translationally not addressed
  8. 2011 High

    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

    PMID:21933716

    Open questions at the time
    • Full-length DII conformation not visualized in the crystal
    • Cofactor-bound regulatory states not captured
  9. 2012 Medium

    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

    PMID:22285491 PMID:22761313 PMID:23002137

    Open questions at the time
    • Conformational states lacked functional mutagenesis validation in the structural paper
    • Direct vs indirect mode of ARF promoter repression unresolved
  10. 2013 High

    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

    PMID:23403462 PMID:23637611 PMID:23858445 PMID:24167278

    Open questions at the time
    • Common molecular principle linking these diverse functions not unified
    • Whether dynein arm assembly requires RUVBL2 ATPase not directly tested
  11. 2014 High

    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

    PMID:24990942 PMID:25428364

    Open questions at the time
    • Whether RUVBL2 chaperones FA core complex assembly or acts catalytically at lesions unclear
  12. 2015 High

    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

    PMID:26303906

    Open questions at the time
    • Whether disaggregation uses the same threading mechanism as classical disaggregases not established
  13. 2017 High

    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

    PMID:28561026 PMID:28591576 PMID:29074727

    Open questions at the time
    • General rules governing which cofactors select RUVBL1 vs RUVBL2 not formalized
  14. 2019 High

    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

    PMID:31049401 PMID:31138842 PMID:31883965

    Open questions at the time
    • Therapeutic window for ATPase inhibition in cancer not defined within these studies
  15. 2020 High

    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

    PMID:32295120 PMID:32376767 PMID:33205750 PMID:33355144 PMID:35635291

    Open questions at the time
    • How a slow ATPase encodes circadian timing not yet mechanistically explained at this stage
    • Generalizability of subunit-specific cofactor action across all complexes untested
  16. 2022 High

    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

    PMID:35178388 PMID:36171202

    Open questions at the time
    • Whether CTD clustering depends on the assembly-chaperone cycle or a distinct activity unclear
  17. 2025 High

    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)

    PMID:40140583 PMID:bio_10.1101_2025.09.11.675549

    Open questions at the time
    • How ATPase turnover rate is read out as circadian period not mechanistically resolved
    • CCDC103-R2C structure is a preprint

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0044183 protein folding chaperone 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9909396 Circadian clock 2
Partners
BMAL1CCDC103DHX34LRRC6PIH1D1RPAP3RUVBL1ZNHIT2
Complex memberships
Fanconi anemia core complexR2TP/PAQosomeSRCAP/TIP60 (H2A.Z exchange) complexγ-tubulin ring complex (γTuRC) assembly intermediate

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Enzyme assays (ATPase, helicase), co-immunoprecipitation, size-exclusion chromatography The Journal of biological chemistry High 10428817
1999 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. Yeast two-hybrid, affinity chromatography, subcellular fractionation Biochimica et biophysica acta Medium 10524211
2000 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. Co-immunoprecipitation, reporter gene assays, Drosophila genetic epistasis The EMBO journal High 11080158
2001 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. Yeast two-hybrid, co-immunoprecipitation, reporter gene assays, mutagenesis Molecular and cellular biology High 11713276
2005 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). Co-immunoprecipitation, Drosophila genetic interaction/epistasis, mitotic clones, reporter assays Proceedings of the National Academy of Sciences of the United States of America High 16087886
2005 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. Immunofluorescence microscopy, subcellular fractionation, cell cycle analysis Experimental cell research Medium 16157330
2006 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. In vitro reconstitution, ATPase assays, site-directed mutagenesis, negative-stain electron microscopy, 3D reconstruction Journal of molecular biology High 17157868
2008 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. In vitro reconstitution, ATPase assays, DNA helicase assays, electron microscopy Journal of molecular biology High 18234224
2009 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. Tandem affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, GLUT4 translocation assay, glucose uptake assay Cell research Medium 19532121
2009 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. Biochemical purification of complexes, in vitro histone exchange assays, ATPase mutants, ChIP Nucleic acids research High 19696079
2010 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). Co-immunoprecipitation, siRNA knockdown, immunoprecipitation of mRNPs, NMD functional assays Science signaling High 20371770
2010 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. DNA binding assays, ATPase assays, helicase assays, sedimentation analysis The FEBS journal Medium 20553504
2011 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. X-ray crystallography, SAXS, ATPase assays, helicase assays, mutagenesis Journal of structural biology High 21933716
2012 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. Cryo-electron microscopy, image classification, 3D reconstruction at ~15 Å Nucleic acids research Medium 23002137
2012 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). ENU chemical mutagenesis forward genetic screen, positional cloning, immunological phenotyping in mice Proceedings of the National Academy of Sciences of the United States of America Medium 22761313
2012 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. Chromatin immunoprecipitation (ChIP), overexpression/knockdown, luciferase reporter assay, western blotting FEBS letters Medium 22285491
2013 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. Co-immunoprecipitation, zebrafish genetics (mutant analysis), immunofluorescence/colocalization, transmission electron microscopy of cilia Proceedings of the National Academy of Sciences of the United States of America High 23858445
2013 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. Co-immunoprecipitation, ChIP, siRNA knockdown, in vivo mouse model of airway inflammation Proceedings of the National Academy of Sciences of the United States of America High 24167278
2013 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. ChIP, siRNA knockdown, 3C (chromosome conformation capture), H2A.Z exchange assays PLoS genetics High 23637611
2013 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. shRNA knockdown, dominant-negative ATPase mutant, telomerase assay, clonogenic assay, cell viability assays Leukemia Medium 23403462
2014 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. Affinity purification/mass spectrometry under native conditions, siRNA knockdown, conditional mouse KO, chromosomal fragility assays, western blotting Nucleic acids research High 25428364
2014 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. Electron microscopy, co-immunoprecipitation, bimolecular fluorescence complementation, ATPase mutant analysis, RAD51 foci immunofluorescence The Journal of biological chemistry Medium 24990942
2015 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. siRNA screen, co-immunoprecipitation, aggresome formation assays, ATPase stimulation assays, protein disaggregation assays, yeast genetics The EMBO journal High 26303906
2017 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. Multiple target affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, proteomics Nature communications High 28561026
2017 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. ATPase assays, mass spectrometry cross-linking, cryo-EM, integrative structural modeling Cell reports High 28591576
2017 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. Conditional knockout mouse model, primary hepatocyte experiments, ATPase inhibitor, western blotting, metabolic phenotyping Gut High 29074727
2019 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. Cryo-electron microscopy, ATPase assays, mutagenesis Science advances High 31049401
2019 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. Specific ATPase inhibitor treatment, PAQosome complex analysis, cell cycle analysis, cell viability assays Cell chemical biology Medium 31883965
2019 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. shRNA knockdown, ChIP-seq, RNA-seq, in vivo xenograft mouse model Leukemia High 31138842
2020 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. Cryo-electron microscopy, heterologous coexpression reconstitution, co-immunoprecipitation, depletion in cells, microtubule nucleation assay Science advances High 33355144
2020 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. Crystal structure determination, spike-in ChIP-seq, co-immunoprecipitation, circadian bioluminescence assay, mouse pharmacology Science translational medicine High 32376767
2020 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. Enzyme kinetics, surface plasmon resonance, size-exclusion chromatography, SAXS Biomolecules Medium 32295120
2020 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). Cryo-electron microscopy, in vitro ATPase assays, co-immunoprecipitation, ATPase-deficient mutants eLife High 33205750
2021 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. Co-immunoprecipitation, reporter gene assay, pharmacological inhibitors, ELISA (EPO), western blotting Biochemical and biophysical research communications Medium 33865222
2022 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. ChIP-seq, rapid degron-mediated depletion (auxin-inducible degron), co-immunoprecipitation, super-resolution microscopy, nascent RNA sequencing Nature communications High 36171202
2022 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. siRNA screening, co-immunoprecipitation, proteomics, subcellular fractionation, fluorescence microscopy Journal of cell science Medium 35635291
2022 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. ENU mutant analysis, CRISPR deletion allele generation, tissue-specific transgenic overexpression, EdU proliferation assay, cardiac regeneration model Frontiers in cell and developmental biology High 35178388
2024 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. Site-directed mutagenesis, biochemical ATPase assays, yeast genetics, molecular dynamics simulations, snoRNP biogenesis assay bioRxivpreprint Medium 38798342
2025 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. AAV delivery of RUVBL2 variants to mouse SCN, enzymatic ATPase assays, co-immunoprecipitation across species, circadian locomotor assay Nature High 40140583
2025 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. Cryo-electron microscopy, biochemical reconstitution, structural analysis bioRxivpreprint High bio_10.1101_2025.09.11.675549
2025 RUVBL2 functions as a replication-specific cofactor for the influenza A virus polymerase, as distinguished from transcription-specific cofactors by differential interactome screening. Differential affinity purification/mass spectrometry interactome screen, functional siRNA knockdown with viral replication assay bioRxivpreprint Low bio_10.1101_2025.06.06.658254

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity. The EMBO journal 238 11080158
2009 RVB1/RVB2: running rings around molecular biology. Molecular cell 194 19524533
2010 AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay. Science signaling 131 20371770
1999 TIP49b, a new RuvB-like DNA helicase, is included in a complex together with another RuvB-like DNA helicase, TIP49a. The Journal of biological chemistry 122 10428817
2011 Structural and functional insights into a dodecameric molecular machine - the RuvBL1/RuvBL2 complex. Journal of structural biology 105 21933716
2017 R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nature communications 96 28561026
2005 Myc interacts genetically with Tip48/Reptin and Tip49/Pontin to control growth and proliferation during Drosophila development. Proceedings of the National Academy of Sciences of the United States of America 86 16087886
2014 Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement. Arthritis care & research 85 24023044
2006 Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex. Journal of molecular biology 85 17157868
2013 Chaperone-like activity of the AAA+ proteins Rvb1 and Rvb2 in the assembly of various complexes. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 83 23530256
2012 A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity. Proceedings of the National Academy of Sciences of the United States of America 81 22761313
2008 Yeast Rvb1 and Rvb2 are ATP-dependent DNA helicases that form a heterohexameric complex. Journal of molecular biology 77 18234224
2001 TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Molecular and cellular biology 66 11713276
2020 RUVBL1-RUVBL2 AAA-ATPase: a versatile scaffold for multiple complexes and functions. Current opinion in structural biology 63 33129013
2019 RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer. Cell chemical biology 60 31883965
2010 Rvb1-Rvb2: essential ATP-dependent helicases for critical complexes. Biochemistry and cell biology = Biochimie et biologie cellulaire 60 20130677
2009 Cooperative action of TIP48 and TIP49 in H2A.Z exchange catalyzed by acetylation of nucleosomal H2A. Nucleic acids research 54 19696079
2011 Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not. Journal of applied physiology (Bethesda, Md. : 1985) 52 21799128
2013 Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility. Proceedings of the National Academy of Sciences of the United States of America 51 23858445
2012 Conformational transitions regulate the exposure of a DNA-binding domain in the RuvBL1-RuvBL2 complex. Nucleic acids research 51 23002137
2020 Assembly of the asymmetric human γ-tubulin ring complex by RUVBL1-RUVBL2 AAA ATPase. Science advances 47 33355144
2015 RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils. The EMBO journal 47 26303906
2005 Relocalization of human chromatin remodeling cofactor TIP48 in mitosis. Experimental cell research 45 16157330
2017 Regulation of Rvb1/Rvb2 by a Domain within the INO80 Chromatin Remodeling Complex Implicates the Yeast Rvbs as Protein Assembly Chaperones. Cell reports 44 28591576
2014 Structure of Yin Yang 1 oligomers that cooperate with RuvBL1-RuvBL2 ATPases. The Journal of biological chemistry 43 24990942
2019 Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM. Science advances 42 31049401
2010 Oligomeric assembly and interactions within the human RuvB-like RuvBL1 and RuvBL2 complexes. The Biochemical journal 39 20412048
2022 The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors. Nature communications 38 36171202
2010 Comparison of the multiple oligomeric structures observed for the Rvb1 and Rvb2 proteins. Biochemistry and cell biology = Biochimie et biologie cellulaire 38 20130681
2020 Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals. Science translational medicine 37 32376767
2014 Abundance of the Fanconi anaemia core complex is regulated by the RuvBL1 and RuvBL2 AAA+ ATPases. Nucleic acids research 36 25428364
2012 Integrated regulation of PIKK-mediated stress responses by AAA+ proteins RUVBL1 and RUVBL2. Nucleus (Austin, Tex.) 35 22540023
2013 TIP48/Reptin and H2A.Z requirement for initiating chromatin remodeling in estrogen-activated transcription. PLoS genetics 33 23637611
2013 The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis. Leukemia 32 23403462
2013 Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression. Proceedings of the National Academy of Sciences of the United States of America 28 24167278
2011 RuvBl2 cooperates with Ets2 to transcriptionally regulate hTERT in colon cancer. FEBS letters 25 21763315
1999 Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins. Biochimica et biophysica acta 25 10524211
2017 Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling. Gut 23 29074727
2020 Sorafenib as an Inhibitor of RUVBL2. Biomolecules 22 32295120
2019 Identification of RUVBL1 and RUVBL2 as Novel Cellular Interactors of the Ebola Virus Nucleoprotein. Viruses 22 31018511
2009 RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation. Cell research 21 19532121
2025 The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes. Nature 20 40140583
2019 The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia. Leukemia 19 31138842
2015 Yeast rvb1 and rvb2 proteins oligomerize as a conformationally variable dodecamer with low frequency. Journal of molecular biology 18 25636407
2020 Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM. eLife 14 33205750
2000 Human TIP49b/RUVBL2 gene: genomic structure, expression pattern, physical link to the human CGB/LHB gene cluster on chromosome 19q13.3. Annales de genetique 14 10998447
2016 Characterizing the mitochondrial DNA polymerase gamma interactome by BioID identifies Ruvbl2 localizes to the mitochondria. Mitochondrion 12 27845271
2016 Proteomic and Genomic Analyses of the Rvb1 and Rvb2 Interaction Network upon Deletion of R2TP Complex Components. Molecular & cellular proteomics : MCP 11 26831523
2013 RuvBL2 is involved in histone deacetylase inhibitor PCI-24781-induced cell death in SK-N-DZ neuroblastoma cells. PloS one 11 23977108
2012 RUVBL2 is a novel repressor of ARF transcription. FEBS letters 11 22285491
2020 PPARγ enhanced Adiponectin polymerization and trafficking by promoting RUVBL2 expression during adipogenic differentiation. Gene 10 32877748
2010 3'- to 5' DNA unwinding by TIP49b proteins. The FEBS journal 10 20553504
2024 Knockdown of RUVBL2 improves hnRNPA2/B1-stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats. Aging cell 8 39610020
2021 Novel HIF-2α interaction with Reptin52 impairs HIF-2 transcriptional activity and EPO secretion. Biochemical and biophysical research communications 8 33865222
2022 Deciphering cellular and molecular determinants of human DPCD protein in complex with RUVBL1/RUVBL2 AAA-ATPases. Journal of molecular biology 7 35901867
2008 Cloning, expression, purification, crystallization and preliminary X-ray analysis of the human RuvBL1-RuvBL2 complex. Acta crystallographica. Section F, Structural biology and crystallization communications 7 18765919
2007 Functional and comparative characterization of Saccharomyces cerevisiae RVB1 and RVB2 genes with bacterial Ruv homologues. FEMS yeast research 7 17302941
2022 Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2. Journal of cell science 6 35635291
2022 Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation. eLife 6 36107469
2009 Reptin52 expression during in vitro neural differentiation of human embryonic stem cells. Neuroscience letters 6 19444951
2016 RuvB-Like Protein 2 (Ruvbl2) Has a Role in Directing the Neuroectodermal Differentiation of Mouse Embryonic Stem Cells. Stem cells and development 5 27469992
2021 Leishmania major RUVBL1 has a hexameric conformation in solution and, in the presence of RUVBL2, forms a heterodimer with ATPase activity. Archives of biochemistry and biophysics 4 33775623
2024 A novel LINC02321 promotes cell proliferation and decreases cisplatin sensitivity in bladder cancer by regulating RUVBL2. Translational oncology 3 38677015
2021 Reptin/RUVBL2 is required for hepatocyte proliferation in vivo, liver regeneration and homeostasis. Liver international : official journal of the International Association for the Study of the Liver 3 33792165
2020 Modeling of a 14 kDa RUVBL2-Binding Domain with Medium Resolution Cryo-EM Density. Journal of chemical information and modeling 3 32175735
2022 Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration. Frontiers in cell and developmental biology 2 35178388
2023 Genetic and chemical targeting of the ATPase complex TIP48 and 49 impairs acute myeloid leukemia. Leukemia 1 37491463
2018 NMR assignment and solution structure of the external DII domain of the yeast Rvb2 protein. Biomolecular NMR assignments 1 29569106
2026 RUVBL2 Regulates Microglia Metabolic Reprogramming to Mediate Stress Granules Aggregation Exacerbating Postoperative Delirium in Aged Mild Cognitive Impairment Rats. Aging cell 0 41931282
2026 RUVBL1 and RUVBL2 are druggable MYC effector regulators in neuroblastoma cells. iScience 0 41940329
2025 Profiling of RUVBL2-Induced Transcriptome Alterations Highlights a Critical Role for Chromatin Remodeling in Ovarian Cancer. BioFactors (Oxford, England) 0 40757751
2025 ASPH interacts with RUVBL2 to promote tumor metastasis in lung adenocarcinoma via MAPK and Notch signaling pathways. Frontiers of medicine 0 41454078
2024 Differential roles of putative arginine fingers of AAA+ ATPases Rvb1 and Rvb2. bioRxiv : the preprint server for biology 0 38798342

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