{"gene":"AQR","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"IBP160 (AQR) binds pre-mRNA in a sequence-independent manner, contacting nucleotides 33-40 upstream of the intron branch site regardless of whether a snoRNA is present. It is the key spliceosomal factor coupling box C/D snoRNP assembly to intron excision; depletion of IBP160 abrogates snoRNP assembly in vitro. Direct binding of IBP160 to a snoRNA located too close to the branch site interferes with snoRNP assembly.","method":"In vitro spliceosomal complex isolation, UV crosslinking/RNA binding assays, depletion experiments, reconstitution","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay with depletion and direct RNA binding mapping, multiple orthogonal methods in single rigorous study","pmids":["16949364"],"is_preprint":false},{"year":2007,"finding":"EJC components are primarily recruited to the spliceosome by association with the intron via IBP160 (AQR). RNAi knockdown of IBP160 arrests EJC association with cytoplasmic RNAs following nonsense-mediated decay, demonstrating that the intron has a crucial role in early steps of EJC formation.","method":"RNAi knockdown, RNA immunoprecipitation, cytoplasmic RNA fractionation","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi knockdown with defined cellular phenotype (arrested EJC deposition), single lab with two orthogonal methods","pmids":["17675447"],"is_preprint":false},{"year":2012,"finding":"AQR (IBP160) is required for localization of MALAT-1 noncoding RNA to nuclear speckles. RNAi-mediated repression of IBP160 results in diffusion of MALAT-1 to the nucleoplasm.","method":"RNAi knockdown, fluorescence localization imaging","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNAi depletion with defined localization phenotype, single lab, replicated across multiple factors","pmids":["22355166"],"is_preprint":false},{"year":2014,"finding":"R-loops induced by depletion of the RNA/DNA helicase AQR (Aquarius) are processed into DNA double-strand breaks by the nucleotide excision repair endonucleases XPF and XPG, and this DSB formation requires the TC-NER factor CSB but not the global genome repair protein XPC.","method":"RNAi knockdown of AQR, DSB assays (gamma-H2AX, comet assay), genetic epistasis with NER factors, R-loop detection","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with knockdown and multiple damage readouts, replicated across multiple RNA processing factors","pmids":["25435140"],"is_preprint":false},{"year":2017,"finding":"AQR depletion in human cells causes R-loop-mediated accumulation of DNA damage during S phase. AQR knockdown decreases Rad51 and RPA foci formation after DNA damage, indicating AQR contributes to homologous recombination repair. AQR knockdown also reduces CtIP protein levels; exogenous AQR expression partially restores CtIP levels, but CtIP overproduction alone does not rescue HR deficiency, suggesting AQR regulates HR via both CtIP-dependent and CtIP-independent pathways.","method":"siRNA knockdown, immunofluorescence foci assays (Rad51, RPA), western blotting, rescue experiments with exogenous AQR and CtIP overexpression, genotoxin sensitivity assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal phenotypic readouts and partial rescue, single lab","pmids":["29061988"],"is_preprint":false},{"year":2017,"finding":"The C. elegans ortholog EMB-4/AQR/IBP160 is enriched along pre-mRNAs of ~8,000 transcripts and plays differential roles in CSR-1 and HRDE-1 nuclear 22G-RNA pathways in the germline. EMB-4 complexes are enriched for both intronic and exonic sequences of HRDE-1 targets, while CSR-1 pathway targets are enriched for intronic but not exonic sequences.","method":"Transcriptome-wide RNA binding analysis (CLIP/RIP-seq), small RNA sequencing, genetic analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide binding mapping plus genetic pathway analysis, single lab, multiple orthogonal methods","pmids":["28787592"],"is_preprint":false},{"year":1998,"finding":"Aquarius (AQR) was identified as a novel gene by gene trap in mouse embryonic stem cells. Its open reading frame contains weak homology to RNA-dependent RNA polymerases and an RRP motif. The gene is expressed in mesoderm, neural crest and its target tissues, and neuroepithelium during embryogenesis.","method":"Gene trap screen with lacZ reporter, expression analysis, FISH chromosomal mapping","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original identification with reporter-based expression analysis and sequence characterization, single lab","pmids":["9626505"],"is_preprint":false},{"year":2020,"finding":"eCLIP analysis resolved AQR association with spliceosomal intermediates after intronic lariat formation, enabling identification of branch points with single-nucleotide resolution and providing genome-wide validation for a branch point-based scanning model for 3' splice site recognition.","method":"eCLIP (enhanced crosslinking and immunoprecipitation) transcriptome-wide mapping in K562 and HepG2 cells","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — eCLIP with single-nucleotide resolution in two cell lines, standardized methodology, genome-wide validation","pmids":["32252787"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structural analysis revealed that catalytic activation of the human spliceosome occurs in two ATP-dependent stages driven by two helicases sequentially: first PRP2, then Aquarius (AQR). Inactivation of AQR leads to stalling of a spliceosome intermediate called the BAQR complex, found halfway through catalytic activation. PRP2 translocates along the intron stripping away the RES complex, opening the SF3B1 clamp, and unfastening the branch helix; AQR then enables dissociation of PRP2 plus SF3A and SF3B complexes, promoting relocation of the branch duplex for catalysis.","method":"Cryo-EM structure determination, helicase inactivation mutants, spliceosome stalling and purification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of stalled intermediate plus helicase inactivation, provides direct structural and mechanistic evidence in single rigorous study","pmids":["37165190"],"is_preprint":false},{"year":2024,"finding":"AQR (intron binding protein) serves as a mediator for Dbr1 recruitment to the branchpoint. Co-immunoprecipitation mass spectrometry identified AQR as a Dbr1 interactor. AQR's position upstream of the branch site in the intron-binding complex facilitates debranching enzyme access to lariats after splicing.","method":"Co-immunoprecipitation mass spectrometry, DBR1 knockout cell line, lariat accumulation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP MS identification of interaction, supported by DBR1 KO phenotypic analysis, single lab","pmids":["38816363"],"is_preprint":false},{"year":2025,"finding":"AQR, as part of the pentameric intron binding complex (IBC), associates with HIV-1 integrase (IN) and its RNA:DNA helicase activity promotes integration into RNA:DNA hybrid (R-loop) substrates in vitro. Knockout of AQR in primary CD4+ T cells impaired overall HIV-1 integration efficiency; remaining integrations mapped to intergenic and R-loop-distal regions.","method":"Co-immunoprecipitation, in vitro integration assay with R-loop substrates, AQR knockout in primary CD4+ T cells, integration site sequencing","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with helicase activity plus KO in primary cells with integration site sequencing, multiple orthogonal methods","pmids":["40836041"],"is_preprint":false},{"year":2022,"finding":"AQR overexpression in human umbilical vein endothelial cells (HUVECs) promotes cellular senescence, evidenced by increased senescence-associated beta-galactosidase staining, upregulation of CDKN1A (P21), inhibited colony formation, and G2/M arrest. Transcriptomic analysis identified PLAU as a co-expressed downstream effector; knockdown of PLAU rescued senescence-related phenotypes induced by AQR or TNF-α. AQR/PLAU signaling axis mediates hyperglycemia-induced endothelial senescence.","method":"AQR overexpression and knockdown in HUVECs, senescence assays (beta-galactosidase, P21, colony formation, cell cycle), transcriptomics, PLAU knockdown rescue experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and knockdown with multiple phenotypic readouts and epistasis rescue, single lab","pmids":["35270021"],"is_preprint":false},{"year":2018,"finding":"Knockdown of AQR in HepG2 cells facilitated glucose uptake, decreased PCK2 expression, increased GSK-3β phosphorylation, restored insulin sensitivity, and inhibited the mTOR pathway and protein ubiquitination process, establishing AQR as a regulator of signaling pathways critical for glucose metabolism.","method":"siRNA knockdown in HepG2 cells, glucose uptake assay, western blotting for signaling components, gene expression analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple pathway readouts, single lab","pmids":["29502958"],"is_preprint":false},{"year":2025,"finding":"AQR knockdown was found to reproduce ~40% of SF3B1 hotspot mutant missplicing defects. However, AQR knockdown caused significant SUGP1 missplicing and reduced SUGP1 protein levels, indicating that AQR loss reproduces mutant SF3B1 splicing defects only indirectly through effects on SUGP1.","method":"Computational screen of 600 splicing proteins, siRNA knockdown, RNA-seq splicing analysis, western blotting for SUGP1","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with transcriptome-wide splicing analysis and mechanistic follow-up showing indirect effect via SUGP1, single lab","pmids":["40714635"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, depletion of IBP160 (AQR ortholog) along with other splicing factors resulted in cytoplasmic leakage of unspliced RNAs. Y14 physical interaction with pre-mRNA and spliceosomal U snRNAs (especially U2 snRNA) was abolished when both IBP160 and PRP19 were depleted, suggesting IBP160 is required for EJC recruitment onto introns and interaction with U2 snRNP to provide a nuclear retention signal for unspliced RNAs.","method":"RNAi depletion in C. elegans, RNA fractionation, RIP (RNA immunoprecipitation), genetic interaction analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with fractionation and RIP assays, genetic interaction analysis, single lab","pmids":["23149939"],"is_preprint":false},{"year":2025,"finding":"AQR is recurrently hemizygously deleted as an early clonal event in cancer genomes, and these deletions are associated with elevated structural variants and point mutation signatures indicative of homologous recombination deficiency. Functional perturbation screens confirm that AQR loss contributes to genomic instability.","method":"Pan-cancer genomic analysis, functional perturbation screens (dependency maps), structural variant and mutation signature analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screens combined with large genomic datasets, but mechanistic details inferred from genomic analysis","pmids":["41719398"],"is_preprint":false}],"current_model":"AQR (Aquarius/IBP160/fSAP164) is a DEAH-box RNA helicase and core component of the spliceosomal intron binding complex (IBC) that drives the second ATP-dependent stage of catalytic spliceosome activation by enabling dissociation of PRP2, SF3A, and SF3B complexes from the lariat intermediate (BAQR complex), while also binding ~33-40 nucleotides upstream of the branch site to couple box C/D snoRNP assembly and EJC deposition to pre-mRNA splicing, resolving R-loops to prevent TC-NER-mediated DSB formation and support homologous recombination repair, recruiting the debranching enzyme Dbr1 to lariats, and facilitating HIV-1 integration into R-loop-enriched genomic regions via its RNA:DNA unwinding activity."},"narrative":{"mechanistic_narrative":"AQR (Aquarius/IBP160) is a DEAH-box RNA/DNA helicase and core component of the spliceosomal intron-binding complex that drives catalytic activation of the spliceosome and couples splicing to downstream RNA and genome-maintenance processes [PMID:16949364, PMID:37165190]. It binds pre-mRNA in a sequence-independent manner ~33–40 nucleotides upstream of the intron branch site [PMID:16949364], and cryo-EM of stalled intermediates places it as the second of two sequentially acting helicases during catalytic activation: after PRP2 strips the RES complex and unfastens the branch helix, AQR enables dissociation of PRP2 along with the SF3A and SF3B complexes, repositioning the branch duplex for catalysis, with its inactivation trapping the BAQR intermediate [PMID:37165190]. Its position upstream of the branch site lets AQR mark introns for downstream events — recruiting EJC components to the intron [PMID:17675447], mediating recruitment of the debranching enzyme Dbr1 to the lariat branchpoint [PMID:38816363], and supporting branch-point-based 3' splice site recognition resolvable to single-nucleotide precision by eCLIP [PMID:32252787]. Through its RNA:DNA unwinding activity AQR resolves co-transcriptional R-loops; its depletion causes R-loop accumulation that is processed into DNA double-strand breaks by the TC-NER endonucleases XPF and XPG in a CSB-dependent manner [PMID:25435140], and AQR loss impairs homologous recombination through Rad51/RPA foci defects and reduced CtIP levels [PMID:29061988]. The same helicase activity is exploited by HIV-1, where AQR within the intron-binding complex associates with viral integrase and promotes integration into R-loop-enriched genomic regions [PMID:40836041]. Recurrent hemizygous deletion of AQR is an early clonal cancer event associated with genomic instability and HR-deficiency signatures [PMID:41719398].","teleology":[{"year":1998,"claim":"Established AQR as a distinct gene and gave the first clue to a nucleic-acid-related function, before any biochemical role was known.","evidence":"Gene-trap identification in mouse ES cells with lacZ expression analysis and chromosomal mapping","pmids":["9626505"],"confidence":"Medium","gaps":["No biochemical activity demonstrated","Sequence homology to RdRP/RRP motif only weak and not functionally tested"]},{"year":2006,"claim":"Defined where AQR engages the spliceosome — binding pre-mRNA sequence-independently 33-40 nt upstream of the branch site — and showed this binding couples box C/D snoRNP assembly to splicing.","evidence":"In vitro spliceosomal complex isolation, UV crosslinking RNA mapping, depletion and reconstitution","pmids":["16949364"],"confidence":"High","gaps":["Catalytic helicase mechanism not yet resolved","Structural placement within spliceosome unknown at this stage"]},{"year":2007,"claim":"Showed AQR/intron binding links splicing to EJC formation, explaining how the intron contributes to downstream mRNA surveillance.","evidence":"RNAi knockdown with RNA immunoprecipitation and cytoplasmic RNA fractionation","pmids":["17675447"],"confidence":"Medium","gaps":["Direct AQR-EJC physical contacts not mapped","Single-lab two-method support"]},{"year":2012,"claim":"Extended AQR function to nuclear RNA organization and unspliced-RNA retention, indicating roles beyond catalysis proper.","evidence":"RNAi knockdown with MALAT-1 localization imaging (human); RNAi depletion with fractionation and RIP genetic interaction analysis (C. elegans)","pmids":["22355166","23149939"],"confidence":"Medium","gaps":["Mechanism of MALAT-1 retention unresolved","Direct vs indirect contribution to nuclear retention not separated"]},{"year":2014,"claim":"Identified AQR as an R-loop-resolving helicase whose loss converts unresolved R-loops into DNA double-strand breaks via a defined TC-NER endonuclease pathway.","evidence":"RNAi knockdown with gamma-H2AX/comet DSB assays and genetic epistasis with XPF, XPG, CSB, XPC","pmids":["25435140"],"confidence":"High","gaps":["Direct helicase action on R-loops not reconstituted in this study","Cell-cycle dependence not resolved here"]},{"year":2017,"claim":"Connected AQR-dependent R-loop control to genome repair, showing AQR supports homologous recombination through CtIP-dependent and -independent routes.","evidence":"siRNA knockdown with Rad51/RPA foci assays, western blotting, rescue with exogenous AQR and CtIP, genotoxin sensitivity","pmids":["29061988"],"confidence":"Medium","gaps":["CtIP-independent HR pathway undefined","Direct vs splicing-mediated effect on repair factors unclear"]},{"year":2017,"claim":"Showed in C. elegans that AQR (EMB-4) binds thousands of pre-mRNAs and differentially feeds nuclear small-RNA (CSR-1, HRDE-1) pathways, linking intron binding to RNA silencing.","evidence":"Transcriptome-wide CLIP/RIP-seq, small RNA sequencing, genetics","pmids":["28787592"],"confidence":"Medium","gaps":["Conservation of small-RNA pathway role to humans not established","Mechanism of intron-vs-exon enrichment difference unexplained"]},{"year":2020,"claim":"Provided genome-wide, single-nucleotide-resolution evidence that AQR associates with post-lariat-formation intermediates, validating a branch-point scanning model for 3' splice site recognition.","evidence":"eCLIP transcriptome-wide mapping in K562 and HepG2 cells","pmids":["32252787"],"confidence":"High","gaps":["Does not establish catalytic step controlled by AQR","Causality of scanning model not tested by perturbation"]},{"year":2023,"claim":"Resolved AQR's precise catalytic role: it is the second of two sequential ATP-dependent helicases that completes spliceosome activation by dissociating PRP2, SF3A and SF3B to reposition the branch duplex.","evidence":"Cryo-EM of the stalled BAQR intermediate with helicase inactivation mutants","pmids":["37165190"],"confidence":"High","gaps":["Structural basis of AQR translocation not fully resolved","Coupling to downstream EJC/Dbr1 recruitment not structurally captured"]},{"year":2024,"claim":"Showed AQR's branch-site position physically licenses debranching, recruiting Dbr1 to lariats for post-splicing intron turnover.","evidence":"Co-IP mass spectrometry, DBR1 knockout cells, lariat accumulation assays","pmids":["38816363"],"confidence":"Medium","gaps":["Direct AQR-Dbr1 contact interface not mapped","Single-lab Co-IP MS"]},{"year":2025,"claim":"Demonstrated that HIV-1 hijacks AQR's RNA:DNA helicase activity within the intron-binding complex to target integration to R-loop-rich genomic regions.","evidence":"Co-IP, in vitro integration on R-loop substrates, AQR knockout in primary CD4+ T cells with integration site sequencing","pmids":["40836041"],"confidence":"High","gaps":["Structural basis of AQR-integrase association unknown","Physiological consequence of redirected integration not addressed"]},{"year":2025,"claim":"Clarified AQR's relationship to SF3B1-mutant splicing and to cancer genome instability — AQR loss phenocopies SF3B1 missplicing indirectly via SUGP1, and recurrent AQR deletion drives HR-deficient genomes.","evidence":"siRNA knockdown with RNA-seq and SUGP1 westerns; pan-cancer genomics with dependency-map perturbation and mutation-signature analysis","pmids":["40714635","41719398"],"confidence":"Medium","gaps":["Direct mechanism linking AQR loss to SUGP1 missplicing unresolved","Mechanistic detail of cancer instability inferred from genomic correlation"]},{"year":null,"claim":"How AQR's distinct activities — spliceosome catalysis, R-loop resolution, and reported metabolic/senescence signaling roles — are mechanistically partitioned remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Whether metabolic (glucose/mTOR) and senescence (PLAU) phenotypes are direct AQR functions or downstream of splicing defects is untested","No structural model unifying RNA-splicing and RNA:DNA helicase modes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[8]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,14]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,7,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,15]}],"complexes":["intron-binding complex (IBC)","spliceosome (BAQR intermediate)","exon junction complex (EJC)"],"partners":["DBR1","PRP2","SF3A","SF3B","HIV-1 INTEGRASE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60306","full_name":"RNA helicase aquarius","aliases":["Intron-binding protein of 160 kDa","IBP160"],"length_aa":1485,"mass_kda":171.3,"function":"Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:25599396, PubMed:28076346, PubMed:28502770). Intron-binding spliceosomal protein required to link pre-mRNA splicing and snoRNP (small nucleolar ribonucleoprotein) biogenesis (PubMed:16949364). Plays a key role in position-dependent assembly of intron-encoded box C/D small snoRNP, splicing being required for snoRNP assembly (PubMed:16949364). May act by helping the folding of the snoRNA sequence. Binds to intron of pre-mRNAs in a sequence-independent manner, contacting the region between snoRNA and the branchpoint of introns (40 nucleotides upstream of the branchpoint) during the late stages of splicing (PubMed:16949364). Has ATP-dependent RNA helicase activity and can unwind double-stranded RNA molecules with a 3' overhang (in vitro) (PubMed:25599396)","subcellular_location":"Nucleus; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/O60306/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AQR","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"PRPF19","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AQR","total_profiled":1310},"omim":[{"mim_id":"610548","title":"AQUARIUS INTRON-BINDING SPLICEOSOMAL FACTOR; AQR","url":"https://www.omim.org/entry/610548"},{"mim_id":"607025","title":"MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE; MELK","url":"https://www.omim.org/entry/607025"},{"mim_id":"600540","title":"TRANSCRIPTION FACTOR Sp4; SP4","url":"https://www.omim.org/entry/600540"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AQR"},"hgnc":{"alias_symbol":["KIAA0560","fSAP164","IBP160"],"prev_symbol":[]},"alphafold":{"accession":"O60306","domains":[{"cath_id":"-","chopping":"171-317","consensus_level":"medium","plddt":92.7095,"start":171,"end":317},{"cath_id":"-","chopping":"324-408","consensus_level":"high","plddt":91.1026,"start":324,"end":408},{"cath_id":"-","chopping":"492-611_618-670","consensus_level":"high","plddt":90.3909,"start":492,"end":670},{"cath_id":"3.40.50.300","chopping":"1136-1380","consensus_level":"high","plddt":90.8369,"start":1136,"end":1380},{"cath_id":"1.20.1050","chopping":"11-122","consensus_level":"medium","plddt":85.3854,"start":11,"end":122}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60306","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60306-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60306-F1-predicted_aligned_error_v6.png","plddt_mean":83.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AQR","jax_strain_url":"https://www.jax.org/strain/search?query=AQR"},"sequence":{"accession":"O60306","fasta_url":"https://rest.uniprot.org/uniprotkb/O60306.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60306/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60306"}},"corpus_meta":[{"pmid":"25435140","id":"PMC_25435140","title":"Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25435140","citation_count":486,"is_preprint":false},{"pmid":"4267208","id":"PMC_4267208","title":"Cell-mediated lympholysis. 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It is the key spliceosomal factor coupling box C/D snoRNP assembly to intron excision; depletion of IBP160 abrogates snoRNP assembly in vitro. Direct binding of IBP160 to a snoRNA located too close to the branch site interferes with snoRNP assembly.\",\n      \"method\": \"In vitro spliceosomal complex isolation, UV crosslinking/RNA binding assays, depletion experiments, reconstitution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay with depletion and direct RNA binding mapping, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16949364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EJC components are primarily recruited to the spliceosome by association with the intron via IBP160 (AQR). RNAi knockdown of IBP160 arrests EJC association with cytoplasmic RNAs following nonsense-mediated decay, demonstrating that the intron has a crucial role in early steps of EJC formation.\",\n      \"method\": \"RNAi knockdown, RNA immunoprecipitation, cytoplasmic RNA fractionation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi knockdown with defined cellular phenotype (arrested EJC deposition), single lab with two orthogonal methods\",\n      \"pmids\": [\"17675447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AQR (IBP160) is required for localization of MALAT-1 noncoding RNA to nuclear speckles. RNAi-mediated repression of IBP160 results in diffusion of MALAT-1 to the nucleoplasm.\",\n      \"method\": \"RNAi knockdown, fluorescence localization imaging\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNAi depletion with defined localization phenotype, single lab, replicated across multiple factors\",\n      \"pmids\": [\"22355166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"R-loops induced by depletion of the RNA/DNA helicase AQR (Aquarius) are processed into DNA double-strand breaks by the nucleotide excision repair endonucleases XPF and XPG, and this DSB formation requires the TC-NER factor CSB but not the global genome repair protein XPC.\",\n      \"method\": \"RNAi knockdown of AQR, DSB assays (gamma-H2AX, comet assay), genetic epistasis with NER factors, R-loop detection\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with knockdown and multiple damage readouts, replicated across multiple RNA processing factors\",\n      \"pmids\": [\"25435140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AQR depletion in human cells causes R-loop-mediated accumulation of DNA damage during S phase. AQR knockdown decreases Rad51 and RPA foci formation after DNA damage, indicating AQR contributes to homologous recombination repair. AQR knockdown also reduces CtIP protein levels; exogenous AQR expression partially restores CtIP levels, but CtIP overproduction alone does not rescue HR deficiency, suggesting AQR regulates HR via both CtIP-dependent and CtIP-independent pathways.\",\n      \"method\": \"siRNA knockdown, immunofluorescence foci assays (Rad51, RPA), western blotting, rescue experiments with exogenous AQR and CtIP overexpression, genotoxin sensitivity assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal phenotypic readouts and partial rescue, single lab\",\n      \"pmids\": [\"29061988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C. elegans ortholog EMB-4/AQR/IBP160 is enriched along pre-mRNAs of ~8,000 transcripts and plays differential roles in CSR-1 and HRDE-1 nuclear 22G-RNA pathways in the germline. EMB-4 complexes are enriched for both intronic and exonic sequences of HRDE-1 targets, while CSR-1 pathway targets are enriched for intronic but not exonic sequences.\",\n      \"method\": \"Transcriptome-wide RNA binding analysis (CLIP/RIP-seq), small RNA sequencing, genetic analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide binding mapping plus genetic pathway analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28787592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Aquarius (AQR) was identified as a novel gene by gene trap in mouse embryonic stem cells. Its open reading frame contains weak homology to RNA-dependent RNA polymerases and an RRP motif. The gene is expressed in mesoderm, neural crest and its target tissues, and neuroepithelium during embryogenesis.\",\n      \"method\": \"Gene trap screen with lacZ reporter, expression analysis, FISH chromosomal mapping\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original identification with reporter-based expression analysis and sequence characterization, single lab\",\n      \"pmids\": [\"9626505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eCLIP analysis resolved AQR association with spliceosomal intermediates after intronic lariat formation, enabling identification of branch points with single-nucleotide resolution and providing genome-wide validation for a branch point-based scanning model for 3' splice site recognition.\",\n      \"method\": \"eCLIP (enhanced crosslinking and immunoprecipitation) transcriptome-wide mapping in K562 and HepG2 cells\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — eCLIP with single-nucleotide resolution in two cell lines, standardized methodology, genome-wide validation\",\n      \"pmids\": [\"32252787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structural analysis revealed that catalytic activation of the human spliceosome occurs in two ATP-dependent stages driven by two helicases sequentially: first PRP2, then Aquarius (AQR). Inactivation of AQR leads to stalling of a spliceosome intermediate called the BAQR complex, found halfway through catalytic activation. PRP2 translocates along the intron stripping away the RES complex, opening the SF3B1 clamp, and unfastening the branch helix; AQR then enables dissociation of PRP2 plus SF3A and SF3B complexes, promoting relocation of the branch duplex for catalysis.\",\n      \"method\": \"Cryo-EM structure determination, helicase inactivation mutants, spliceosome stalling and purification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of stalled intermediate plus helicase inactivation, provides direct structural and mechanistic evidence in single rigorous study\",\n      \"pmids\": [\"37165190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AQR (intron binding protein) serves as a mediator for Dbr1 recruitment to the branchpoint. Co-immunoprecipitation mass spectrometry identified AQR as a Dbr1 interactor. AQR's position upstream of the branch site in the intron-binding complex facilitates debranching enzyme access to lariats after splicing.\",\n      \"method\": \"Co-immunoprecipitation mass spectrometry, DBR1 knockout cell line, lariat accumulation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP MS identification of interaction, supported by DBR1 KO phenotypic analysis, single lab\",\n      \"pmids\": [\"38816363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AQR, as part of the pentameric intron binding complex (IBC), associates with HIV-1 integrase (IN) and its RNA:DNA helicase activity promotes integration into RNA:DNA hybrid (R-loop) substrates in vitro. Knockout of AQR in primary CD4+ T cells impaired overall HIV-1 integration efficiency; remaining integrations mapped to intergenic and R-loop-distal regions.\",\n      \"method\": \"Co-immunoprecipitation, in vitro integration assay with R-loop substrates, AQR knockout in primary CD4+ T cells, integration site sequencing\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with helicase activity plus KO in primary cells with integration site sequencing, multiple orthogonal methods\",\n      \"pmids\": [\"40836041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AQR overexpression in human umbilical vein endothelial cells (HUVECs) promotes cellular senescence, evidenced by increased senescence-associated beta-galactosidase staining, upregulation of CDKN1A (P21), inhibited colony formation, and G2/M arrest. Transcriptomic analysis identified PLAU as a co-expressed downstream effector; knockdown of PLAU rescued senescence-related phenotypes induced by AQR or TNF-α. AQR/PLAU signaling axis mediates hyperglycemia-induced endothelial senescence.\",\n      \"method\": \"AQR overexpression and knockdown in HUVECs, senescence assays (beta-galactosidase, P21, colony formation, cell cycle), transcriptomics, PLAU knockdown rescue experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and knockdown with multiple phenotypic readouts and epistasis rescue, single lab\",\n      \"pmids\": [\"35270021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of AQR in HepG2 cells facilitated glucose uptake, decreased PCK2 expression, increased GSK-3β phosphorylation, restored insulin sensitivity, and inhibited the mTOR pathway and protein ubiquitination process, establishing AQR as a regulator of signaling pathways critical for glucose metabolism.\",\n      \"method\": \"siRNA knockdown in HepG2 cells, glucose uptake assay, western blotting for signaling components, gene expression analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple pathway readouts, single lab\",\n      \"pmids\": [\"29502958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AQR knockdown was found to reproduce ~40% of SF3B1 hotspot mutant missplicing defects. However, AQR knockdown caused significant SUGP1 missplicing and reduced SUGP1 protein levels, indicating that AQR loss reproduces mutant SF3B1 splicing defects only indirectly through effects on SUGP1.\",\n      \"method\": \"Computational screen of 600 splicing proteins, siRNA knockdown, RNA-seq splicing analysis, western blotting for SUGP1\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with transcriptome-wide splicing analysis and mechanistic follow-up showing indirect effect via SUGP1, single lab\",\n      \"pmids\": [\"40714635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, depletion of IBP160 (AQR ortholog) along with other splicing factors resulted in cytoplasmic leakage of unspliced RNAs. Y14 physical interaction with pre-mRNA and spliceosomal U snRNAs (especially U2 snRNA) was abolished when both IBP160 and PRP19 were depleted, suggesting IBP160 is required for EJC recruitment onto introns and interaction with U2 snRNP to provide a nuclear retention signal for unspliced RNAs.\",\n      \"method\": \"RNAi depletion in C. elegans, RNA fractionation, RIP (RNA immunoprecipitation), genetic interaction analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with fractionation and RIP assays, genetic interaction analysis, single lab\",\n      \"pmids\": [\"23149939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AQR is recurrently hemizygously deleted as an early clonal event in cancer genomes, and these deletions are associated with elevated structural variants and point mutation signatures indicative of homologous recombination deficiency. Functional perturbation screens confirm that AQR loss contributes to genomic instability.\",\n      \"method\": \"Pan-cancer genomic analysis, functional perturbation screens (dependency maps), structural variant and mutation signature analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screens combined with large genomic datasets, but mechanistic details inferred from genomic analysis\",\n      \"pmids\": [\"41719398\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AQR (Aquarius/IBP160/fSAP164) is a DEAH-box RNA helicase and core component of the spliceosomal intron binding complex (IBC) that drives the second ATP-dependent stage of catalytic spliceosome activation by enabling dissociation of PRP2, SF3A, and SF3B complexes from the lariat intermediate (BAQR complex), while also binding ~33-40 nucleotides upstream of the branch site to couple box C/D snoRNP assembly and EJC deposition to pre-mRNA splicing, resolving R-loops to prevent TC-NER-mediated DSB formation and support homologous recombination repair, recruiting the debranching enzyme Dbr1 to lariats, and facilitating HIV-1 integration into R-loop-enriched genomic regions via its RNA:DNA unwinding activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AQR (Aquarius/IBP160) is a DEAH-box RNA/DNA helicase and core component of the spliceosomal intron-binding complex that drives catalytic activation of the spliceosome and couples splicing to downstream RNA and genome-maintenance processes [#0, #8]. It binds pre-mRNA in a sequence-independent manner ~33–40 nucleotides upstream of the intron branch site [#0], and cryo-EM of stalled intermediates places it as the second of two sequentially acting helicases during catalytic activation: after PRP2 strips the RES complex and unfastens the branch helix, AQR enables dissociation of PRP2 along with the SF3A and SF3B complexes, repositioning the branch duplex for catalysis, with its inactivation trapping the BAQR intermediate [#8]. Its position upstream of the branch site lets AQR mark introns for downstream events — recruiting EJC components to the intron [#1], mediating recruitment of the debranching enzyme Dbr1 to the lariat branchpoint [#9], and supporting branch-point-based 3' splice site recognition resolvable to single-nucleotide precision by eCLIP [#7]. Through its RNA:DNA unwinding activity AQR resolves co-transcriptional R-loops; its depletion causes R-loop accumulation that is processed into DNA double-strand breaks by the TC-NER endonucleases XPF and XPG in a CSB-dependent manner [#3], and AQR loss impairs homologous recombination through Rad51/RPA foci defects and reduced CtIP levels [#4]. The same helicase activity is exploited by HIV-1, where AQR within the intron-binding complex associates with viral integrase and promotes integration into R-loop-enriched genomic regions [#10]. Recurrent hemizygous deletion of AQR is an early clonal cancer event associated with genomic instability and HR-deficiency signatures [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established AQR as a distinct gene and gave the first clue to a nucleic-acid-related function, before any biochemical role was known.\",\n      \"evidence\": \"Gene-trap identification in mouse ES cells with lacZ expression analysis and chromosomal mapping\",\n      \"pmids\": [\"9626505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical activity demonstrated\", \"Sequence homology to RdRP/RRP motif only weak and not functionally tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined where AQR engages the spliceosome — binding pre-mRNA sequence-independently 33-40 nt upstream of the branch site — and showed this binding couples box C/D snoRNP assembly to splicing.\",\n      \"evidence\": \"In vitro spliceosomal complex isolation, UV crosslinking RNA mapping, depletion and reconstitution\",\n      \"pmids\": [\"16949364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic helicase mechanism not yet resolved\", \"Structural placement within spliceosome unknown at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed AQR/intron binding links splicing to EJC formation, explaining how the intron contributes to downstream mRNA surveillance.\",\n      \"evidence\": \"RNAi knockdown with RNA immunoprecipitation and cytoplasmic RNA fractionation\",\n      \"pmids\": [\"17675447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AQR-EJC physical contacts not mapped\", \"Single-lab two-method support\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended AQR function to nuclear RNA organization and unspliced-RNA retention, indicating roles beyond catalysis proper.\",\n      \"evidence\": \"RNAi knockdown with MALAT-1 localization imaging (human); RNAi depletion with fractionation and RIP genetic interaction analysis (C. elegans)\",\n      \"pmids\": [\"22355166\", \"23149939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MALAT-1 retention unresolved\", \"Direct vs indirect contribution to nuclear retention not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified AQR as an R-loop-resolving helicase whose loss converts unresolved R-loops into DNA double-strand breaks via a defined TC-NER endonuclease pathway.\",\n      \"evidence\": \"RNAi knockdown with gamma-H2AX/comet DSB assays and genetic epistasis with XPF, XPG, CSB, XPC\",\n      \"pmids\": [\"25435140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct helicase action on R-loops not reconstituted in this study\", \"Cell-cycle dependence not resolved here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected AQR-dependent R-loop control to genome repair, showing AQR supports homologous recombination through CtIP-dependent and -independent routes.\",\n      \"evidence\": \"siRNA knockdown with Rad51/RPA foci assays, western blotting, rescue with exogenous AQR and CtIP, genotoxin sensitivity\",\n      \"pmids\": [\"29061988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CtIP-independent HR pathway undefined\", \"Direct vs splicing-mediated effect on repair factors unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed in C. elegans that AQR (EMB-4) binds thousands of pre-mRNAs and differentially feeds nuclear small-RNA (CSR-1, HRDE-1) pathways, linking intron binding to RNA silencing.\",\n      \"evidence\": \"Transcriptome-wide CLIP/RIP-seq, small RNA sequencing, genetics\",\n      \"pmids\": [\"28787592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of small-RNA pathway role to humans not established\", \"Mechanism of intron-vs-exon enrichment difference unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided genome-wide, single-nucleotide-resolution evidence that AQR associates with post-lariat-formation intermediates, validating a branch-point scanning model for 3' splice site recognition.\",\n      \"evidence\": \"eCLIP transcriptome-wide mapping in K562 and HepG2 cells\",\n      \"pmids\": [\"32252787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish catalytic step controlled by AQR\", \"Causality of scanning model not tested by perturbation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved AQR's precise catalytic role: it is the second of two sequential ATP-dependent helicases that completes spliceosome activation by dissociating PRP2, SF3A and SF3B to reposition the branch duplex.\",\n      \"evidence\": \"Cryo-EM of the stalled BAQR intermediate with helicase inactivation mutants\",\n      \"pmids\": [\"37165190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AQR translocation not fully resolved\", \"Coupling to downstream EJC/Dbr1 recruitment not structurally captured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed AQR's branch-site position physically licenses debranching, recruiting Dbr1 to lariats for post-splicing intron turnover.\",\n      \"evidence\": \"Co-IP mass spectrometry, DBR1 knockout cells, lariat accumulation assays\",\n      \"pmids\": [\"38816363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AQR-Dbr1 contact interface not mapped\", \"Single-lab Co-IP MS\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that HIV-1 hijacks AQR's RNA:DNA helicase activity within the intron-binding complex to target integration to R-loop-rich genomic regions.\",\n      \"evidence\": \"Co-IP, in vitro integration on R-loop substrates, AQR knockout in primary CD4+ T cells with integration site sequencing\",\n      \"pmids\": [\"40836041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AQR-integrase association unknown\", \"Physiological consequence of redirected integration not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified AQR's relationship to SF3B1-mutant splicing and to cancer genome instability — AQR loss phenocopies SF3B1 missplicing indirectly via SUGP1, and recurrent AQR deletion drives HR-deficient genomes.\",\n      \"evidence\": \"siRNA knockdown with RNA-seq and SUGP1 westerns; pan-cancer genomics with dependency-map perturbation and mutation-signature analysis\",\n      \"pmids\": [\"40714635\", \"41719398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking AQR loss to SUGP1 missplicing unresolved\", \"Mechanistic detail of cancer instability inferred from genomic correlation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AQR's distinct activities — spliceosome catalysis, R-loop resolution, and reported metabolic/senescence signaling roles — are mechanistically partitioned remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metabolic (glucose/mTOR) and senescence (PLAU) phenotypes are direct AQR functions or downstream of splicing defects is untested\", \"No structural model unifying RNA-splicing and RNA:DNA helicase modes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"complexes\": [\n      \"intron-binding complex (IBC)\",\n      \"spliceosome (BAQR intermediate)\",\n      \"exon junction complex (EJC)\"\n    ],\n    \"partners\": [\n      \"DBR1\",\n      \"PRP2\",\n      \"SF3A\",\n      \"SF3B\",\n      \"HIV-1 integrase\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}