{"gene":"NVL","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"NVL encodes an ~110-kDa nuclear protein with two highly similar ATP-binding domains, establishing it as a member of the AAA ATPase family localized to the nucleus.","method":"Degenerate PCR cloning, cDNA sequencing, nuclear localization confirmed by protein characterization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — initial cloning and nuclear localization by protein characterization, single lab, foundational identification study","pmids":["9286697"],"is_preprint":false},{"year":2004,"finding":"NVL2 (the major isoform with a longer N-terminal extension) localizes to the nucleolus, whereas NVL1 is nucleoplasmic. Mutational analysis identified two nuclear localization signals and a distinct nucleolar localization signal (NoLS) within NVL2's N-terminal extra region.","method":"Mutational analysis, subcellular fractionation, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutational analysis with multiple mutants, direct imaging, replicated across NVL1 vs NVL2 comparison","pmids":["15469983"],"is_preprint":false},{"year":2004,"finding":"NVL2 interacts with ribosomal protein L5 through its nucleolar localization signal; this interaction is ATP-dependent and contributes to nucleolar translocation of NVL2. A dominant-negative NVL2 mutant inhibits ribosome biosynthesis.","method":"Yeast two-hybrid screening, co-immunoprecipitation, dominant-negative overexpression with ribosome biosynthesis readout","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus functional dominant-negative assay, multiple orthogonal methods in one study","pmids":["15469983"],"is_preprint":false},{"year":2006,"finding":"NVL2 is associated with pre-ribosomal particles in the nucleus and interacts with the DExD/H-box RNA helicase DOB1/MTR4. This interaction requires the first ATP-binding module of NVL2; a dominant-negative second-module mutant causes aberrant retention of DOB1 on pre-ribosomal particles, suggesting NVL2 regulates association/dissociation of DOB1 from these particles.","method":"Yeast two-hybrid, co-immunoprecipitation, ATPase domain mutagenesis, cellular overexpression of dominant-negative mutants","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, domain mutagenesis, functional dominant-negative assay in multiple orthogonal methods","pmids":["16782053"],"is_preprint":false},{"year":2011,"finding":"The solution structure of the N-terminal unique domain of NVL2 (NVL2-UD) was determined by NMR and found to adopt a winged-helix-like fold distinct from VCP/p97. NVL2-UD binds nucleolin from HeLa extracts in an RNA-dependent manner, with RRKR basic residues in a characteristic loop being necessary and sufficient for nucleolin-RNA complex binding and nucleolar localization.","method":"NMR structure determination, binding assays with HeLa cell extracts, mutagenesis of RRKR residues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus mutagenesis plus binding assay, multiple orthogonal methods, single lab","pmids":["21474449"],"is_preprint":false},{"year":2011,"finding":"NVL2 interacts with hTERT (human telomerase reverse transcriptase) in the nucleolus and is found in association with catalytically competent telomerase. Depletion of NVL2 by siRNA decreases hTERT protein levels (without affecting hTERT mRNA) and reduces telomerase activity. ATP-binding activity of NVL2 is required for hTERT binding and telomerase assembly.","method":"Co-immunoprecipitation, co-localization, siRNA knockdown, TRAP assay for telomerase activity, RT-qPCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockdown with enzymatic activity readout, ATP-binding mutant analysis, single lab with multiple methods","pmids":["22226966"],"is_preprint":false},{"year":2015,"finding":"NVL2 is associated with the nuclear exosome complex (including RRP6 as a nucleus-specific catalytic subunit). This interaction is mediated by MTR4 and RRP6, as depletion of either prevents NVL2-exosome association. MPP6 (another exosome cofactor) is also required, as its knockdown causes MTR4 to dissociate from the nuclear exosome. ATPase domain mutations in NVL2 cause defects in pre-rRNA processing into mature 28S and 5.8S rRNAs.","method":"Co-immunoprecipitation, siRNA knockdown, ATPase domain mutagenesis, northern blotting/rRNA processing assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs with knockdowns plus domain mutagenesis plus pre-rRNA processing readout, multiple orthogonal methods","pmids":["26166824"],"is_preprint":false},{"year":2015,"finding":"NVL2 acts on the MTR4-exosome complex to stimulate ATP hydrolysis-dependent dissociation of WDR74 (a WD repeat protein with similarity to yeast Nsa1). Knockdown of WDR74 decreases 60S ribosome levels, and WDR74 co-localizes with NVL2 in the nucleolus.","method":"Proteomic screen, co-immunoprecipitation, ATPase-deficient NVL2 mutant, siRNA knockdown, ribosome profiling","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic screen plus Co-IP with domain mutant plus knockdown and functional readout, multiple orthogonal methods","pmids":["26456651"],"is_preprint":false},{"year":2017,"finding":"WDR74 knockdown causes defects in pre-rRNA cleavage within ITS1, an early step in the 60S processing pathway. Expression of ATPase-deficient NVL2 also causes the same ITS1 processing defect with partial redistribution of WDR74 from nucleolus to nucleoplasm, where increased WDR74-MTR4 interaction is detected. This establishes that NVL2 ATPase activity spatiotemporally regulates WDR74 dissociation from the MTR4-exosome complex for proper pre-60S maturation.","method":"siRNA knockdown, dominant-negative NVL2 overexpression, northern blotting for pre-rRNA processing, in situ proximity ligation assay, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockdown plus dominant-negative mutant plus proximity ligation assay plus pre-rRNA processing, multiple orthogonal methods","pmids":["29107693"],"is_preprint":false},{"year":2021,"finding":"SPF30 (a Tudor domain-containing pre-mRNA splicing factor) is an MTR4-interacting protein whose association with the MTR4-exosome complex is regulated by NVL2 ATPase activity, analogous to WDR74. The interaction between SPF30 and the exosome core is mediated by MTR4 and RRP6. Knockdown of SPF30 caused a subtle delay in 12S pre-rRNA processing to mature 5.8S rRNA.","method":"Co-immunoprecipitation, siRNA knockdown, shotgun proteomics (interactome), rRNA processing assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus shotgun proteomics plus knockdown functional readout, single lab with multiple methods","pmids":["33422691"],"is_preprint":false},{"year":2024,"finding":"WDR74 functions as part of a pre-ribosomal subcomplex (the WDR74 module) consisting of WDR74, RPF1, MAK16, and RRP1. Each component is mutually required for the interaction of the others with MTR4. NVL2 dysfunction (ATP hydrolysis-deficient mutant) prevents MTR4 from recruiting PICT1 (an MTR4 adaptor required for 5.8S rRNA 3'-end maturation) by blocking release of the WDR74 module from the MTR4-exosome complex.","method":"Co-immunoprecipitation combined with mass spectrometry, siRNA knockdown, pre-rRNA processing assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP/MS plus individual knockdowns plus functional pre-rRNA processing readouts, multiple orthogonal methods in one study","pmids":["39706051"],"is_preprint":false},{"year":2025,"finding":"A small molecule inhibitor MM17 (dibenzothiazepinone) binds NVL at two sites on the hexameric assembly as revealed by cryo-EM. Mutations in NVL at these sites confer resistance to MM17. NVL inhibition arrests 60S ribosome biogenesis in the nucleolus and induces cell cycle arrest or apoptosis via MDM2/p53-dependent and p53-independent pathways without causing DNA damage. A bioavailable analog MM927 suppresses tumor growth in mouse leukemia and colorectal cancer models.","method":"Forward genetics (resistance mutations), cryo-EM structure of NVL hexamer with inhibitor, in vitro and cellular inhibitor treatment, MDM2/p53 pathway analysis, mouse tumor models","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus resistance genetics plus mechanistic pathway dissection plus in vivo validation, multiple orthogonal methods","pmids":["40766499"],"is_preprint":true},{"year":2025,"finding":"CWF19L2 is a novel NVL2-interacting protein that associates with intron lariat spliceosome (ILS) components, lariat RNA debranching enzyme DBR1, and the MTR4-RNA exosome complex. CWF19L2 is required for debranching of intron-derived lariat RNAs, functioning as potently as DBR1 itself.","method":"Co-immunoprecipitation, RNA debranching assay (minigene splicing reporter, RT-PCR for endogenous lariat RNA), super-resolution immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional debranching assay plus imaging, single lab with multiple orthogonal methods","pmids":["41422678"],"is_preprint":false}],"current_model":"NVL2 is a nucleolar AAA-ATPase that forms hexameric assemblies and functions as a chaperone-like remodeling factor during 60S ribosomal subunit biogenesis: it uses ATP hydrolysis to drive the dissociation of processing factors (WDR74 module, SPF30, DOB1/MTR4) from pre-ribosomal particles and the nuclear exosome complex, thereby coordinating sequential pre-rRNA cleavage and processing steps; it also associates with hTERT to support telomerase holoenzyme assembly, interacts with nucleolin-RNA complexes via its structurally unique N-terminal domain, and its inhibition by small molecules (MM17/MM927) arrests 60S biogenesis and triggers MDM2/p53-dependent apoptosis."},"narrative":{"mechanistic_narrative":"NVL encodes a nuclear AAA-ATPase whose major isoform, NVL2, is targeted to the nucleolus and operates as an energy-dependent remodeling factor in ribosome biogenesis [PMID:9286697, PMID:15469983]. NVL2 associates with pre-ribosomal particles and engages the ribosomal protein L5 and the DExD/H-box helicase MTR4/DOB1 through its ATP-binding modules; ATPase activity drives the controlled release of processing factors from these particles, and ATPase-deficient mutants cause aberrant retention of MTR4 and defective maturation of 28S and 5.8S rRNAs [PMID:15469983, PMID:16782053, PMID:26166824]. Acting on the MTR4-nuclear exosome complex, NVL2 stimulates ATP hydrolysis-dependent dissociation of a WDR74 module (WDR74-RPF1-MAK16-RRP1) and of the splicing factor SPF30, thereby controlling early ITS1 cleavage and licensing recruitment of the adaptor PICT1 for 5.8S 3'-end maturation during 60S subunit assembly [PMID:26456651, PMID:29107693, PMID:33422691, PMID:39706051]. A structurally distinct N-terminal winged-helix domain anchors NVL2 to the nucleolus by binding nucleolin-RNA complexes via an RRKR loop, and NVL2 additionally associates with hTERT to support telomerase holoenzyme assembly and activity [PMID:21474449, PMID:22226966]. Small-molecule inhibition of the NVL hexamer arrests nucleolar 60S biogenesis and triggers MDM2/p53-dependent and p53-independent cell-cycle arrest or apoptosis [PMID:40766499].","teleology":[{"year":1997,"claim":"Established the gene product's basic identity—an unknown nuclear protein was defined as a two-domain AAA-ATPase, framing all subsequent mechanistic work around ATP-driven remodeling.","evidence":"Degenerate PCR cloning, cDNA sequencing and nuclear localization by protein characterization","pmids":["9286697"],"confidence":"Medium","gaps":["No substrate or pathway assigned","No subnuclear resolution beyond bulk nuclear localization"]},{"year":2004,"claim":"Resolved why NVL has two functional forms and connected it to ribosome production—NVL2's N-terminal extension carries a nucleolar localization signal and mediates ATP-dependent binding to ribosomal protein L5, with a dominant-negative mutant blocking ribosome biosynthesis.","evidence":"Mutational analysis, subcellular fractionation, fluorescence microscopy, yeast two-hybrid and Co-IP with dominant-negative ribosome readout","pmids":["15469983"],"confidence":"High","gaps":["Step of ribosome biogenesis affected not defined","Biochemical role of ATP hydrolysis vs binding unresolved"]},{"year":2006,"claim":"Identified the first direct enzymatic substrate-like partner—NVL2 binds MTR4/DOB1 via its first ATP module, and a second-module mutant traps DOB1 on pre-ribosomal particles, establishing NVL2 as a regulator of factor association/dissociation.","evidence":"Yeast two-hybrid, reciprocal Co-IP, ATPase domain mutagenesis, dominant-negative overexpression","pmids":["16782053"],"confidence":"High","gaps":["Direct ATP-driven remodeling not reconstituted in vitro","Distinct roles of the two ATP modules not fully separated"]},{"year":2011,"claim":"Defined the structural basis of nucleolar targeting and revealed a second functional axis—an NMR structure showed a unique winged-helix N-terminal domain whose RRKR loop binds nucleolin-RNA complexes, while a separate study linked NVL2 to hTERT and telomerase assembly.","evidence":"NMR structure determination, RRKR mutagenesis, HeLa extract binding assays; Co-IP, siRNA knockdown and TRAP telomerase activity assay","pmids":["21474449","22226966"],"confidence":"High","gaps":["Mechanistic link between nucleolin binding and ribosome remodeling unclear","How NVL2 promotes hTERT stability/telomerase assembly mechanistically undefined"]},{"year":2015,"claim":"Placed NVL2 within the nuclear exosome machinery and tied its ATPase to rRNA maturation—NVL2 joins the MTR4-exosome (RRP6, MPP6) and, via ATP hydrolysis, drives dissociation of the 60S factor WDR74, with ATPase mutants causing 28S/5.8S processing defects.","evidence":"Co-IP with knockdowns of MTR4/RRP6/MPP6, ATPase domain mutagenesis, northern blotting, proteomic screen and ribosome profiling","pmids":["26166824","26456651"],"confidence":"High","gaps":["Order of WDR74 release relative to other steps not defined","In vitro reconstitution of ATP-driven dissociation absent"]},{"year":2017,"claim":"Provided spatiotemporal mechanism—NVL2 ATPase activity controls where and when WDR74 detaches from the MTR4-exosome, with ATPase-deficient NVL2 redistributing WDR74 to the nucleoplasm and blocking ITS1 cleavage, an early 60S step.","evidence":"siRNA knockdown, dominant-negative NVL2, northern blotting, in situ proximity ligation assay, immunofluorescence","pmids":["29107693"],"confidence":"High","gaps":["Downstream consequences of mislocalized WDR74 on later maturation not traced","Coupling between cleavage and factor release mechanistically incomplete"]},{"year":2021,"claim":"Generalized the remodeling model to additional clients—SPF30 was shown to be an MTR4-exosome-associated factor whose release is NVL2 ATPase-regulated like WDR74, with knockdown delaying 12S-to-5.8S processing.","evidence":"Co-IP, shotgun proteomics, siRNA knockdown, rRNA processing assay","pmids":["33422691"],"confidence":"Medium","gaps":["Functional significance of subtle processing delay unclear","Direct ATP-dependence of SPF30 release not shown by mutant in this study"]},{"year":2024,"claim":"Defined the substrate as a multiprotein module and its downstream coupling—WDR74 acts within a WDR74-RPF1-MAK16-RRP1 subcomplex, and NVL2 ATPase failure blocks module release and prevents MTR4 from recruiting the PICT1 adaptor needed for 5.8S 3'-end maturation.","evidence":"Co-IP/mass spectrometry, individual siRNA knockdowns, pre-rRNA processing assays","pmids":["39706051"],"confidence":"High","gaps":["Structural basis of module recognition by NVL2 unknown","Whether NVL2 directly contacts PICT1 unresolved"]},{"year":2025,"claim":"Delivered structural and therapeutic validation—a cryo-EM structure of the NVL hexamer bound to inhibitor MM17 (confirmed by resistance mutations) showed that blocking NVL arrests nucleolar 60S biogenesis and induces MDM2/p53-dependent and -independent death, with an analog suppressing tumors in vivo; CWF19L2 was identified as a new NVL2 partner linking it to lariat RNA debranching.","evidence":"Cryo-EM, forward-genetics resistance mutations, cellular and mouse tumor models, p53 pathway analysis (preprint); Co-IP, RNA debranching assays, super-resolution imaging","pmids":["40766499","41422678"],"confidence":"High","gaps":["MM17/MM927 results are from a preprint pending peer review","Mechanistic role of CWF19L2-NVL2 association in debranching vs ribosome biogenesis not separated"]},{"year":null,"claim":"How NVL2 ATP hydrolysis is mechanically coupled to client release on pre-ribosomal particles, and whether its ribosome-biogenesis and telomerase roles are mechanistically linked, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vitro reconstitution of ATP-driven factor dissociation","Structural basis for substrate engagement by the hexamer incompletely defined","Relationship between nucleolin/hTERT binding and 60S remodeling unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,3,6,7,8,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,8,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,2,4,5,7,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,6,7,8,10]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11]}],"complexes":["MTR4-nuclear exosome complex","WDR74 module (WDR74-RPF1-MAK16-RRP1)","telomerase holoenzyme"],"partners":["MTR4","RRP6","MPP6","WDR74","SPF30","HTERT","RPL5","CWF19L2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15381","full_name":"Nuclear valosin-containing protein-like","aliases":[],"length_aa":856,"mass_kda":95.1,"function":"Participates in the assembly of the telomerase holoenzyme and effecting of telomerase activity via its interaction with TERT (PubMed:22226966). Involved in both early and late stages of the pre-rRNA processing pathways (PubMed:26166824). Spatiotemporally regulates 60S ribosomal subunit biogenesis in the nucleolus (PubMed:15469983, PubMed:16782053, PubMed:26456651, PubMed:29107693). Catalyzes the release of specific assembly factors, such as WDR74, from pre-60S ribosomal particles through the ATPase activity (PubMed:26456651, PubMed:28416111, PubMed:29107693)","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/O15381/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NVL","classification":"Common Essential","n_dependent_lines":1192,"n_total_lines":1208,"dependency_fraction":0.9867549668874173},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143748","cell_line_id":"CID001095","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"ATP5H","stoichiometry":10.0},{"gene":"PHF10","stoichiometry":10.0},{"gene":"PNPT1","stoichiometry":0.2},{"gene":"NDUFV2","stoichiometry":0.2},{"gene":"PMPCB","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001095","total_profiled":1310},"omim":[{"mim_id":"617947","title":"WD REPEAT-CONTAINING PROTEIN 74; WDR74","url":"https://www.omim.org/entry/617947"},{"mim_id":"609820","title":"ERYTHROCYTOSIS, FAMILIAL, 3; ECYT3","url":"https://www.omim.org/entry/609820"},{"mim_id":"609070","title":"HEMOGLOBIN, HIGH ALTITUDE ADAPTATION; HALAH","url":"https://www.omim.org/entry/609070"},{"mim_id":"606425","title":"EGL9 FAMILY HYPOXIA-INDUCIBLE FACTOR 1; EGLN1","url":"https://www.omim.org/entry/606425"},{"mim_id":"602426","title":"NUCLEAR VALOSIN-CONTAINING PROTEIN-LIKE; NVL","url":"https://www.omim.org/entry/602426"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NVL"},"hgnc":{"alias_symbol":["NVL2"],"prev_symbol":[]},"alphafold":{"accession":"O15381","domains":[{"cath_id":"1.10.10.2010","chopping":"12-82","consensus_level":"high","plddt":78.0693,"start":12,"end":82},{"cath_id":"3.40.50.300","chopping":"265-434","consensus_level":"high","plddt":85.8843,"start":265,"end":434},{"cath_id":"1.10.8.60","chopping":"436-496_548-571","consensus_level":"medium","plddt":84.5265,"start":436,"end":571},{"cath_id":"3.40.50.300","chopping":"581-746","consensus_level":"high","plddt":85.2679,"start":581,"end":746},{"cath_id":"1.10.8.60","chopping":"752-839","consensus_level":"high","plddt":86.6586,"start":752,"end":839}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15381","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15381-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15381-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NVL","jax_strain_url":"https://www.jax.org/strain/search?query=NVL"},"sequence":{"accession":"O15381","fasta_url":"https://rest.uniprot.org/uniprotkb/O15381.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15381/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15381"}},"corpus_meta":[{"pmid":"15469983","id":"PMC_15469983","title":"NVL2 is a nucleolar AAA-ATPase that interacts with ribosomal protein L5 through its nucleolar localization sequence.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15469983","citation_count":45,"is_preprint":false},{"pmid":"34365220","id":"PMC_34365220","title":"Will the clinical development of 4th-generation \"double mutant active\" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?","date":"2021","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34365220","citation_count":44,"is_preprint":false},{"pmid":"39269178","id":"PMC_39269178","title":"NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.","date":"2024","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39269178","citation_count":41,"is_preprint":false},{"pmid":"16782053","id":"PMC_16782053","title":"The AAA-ATPase NVL2 is a component of pre-ribosomal particles that interacts with the DExD/H-box RNA helicase DOB1.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16782053","citation_count":33,"is_preprint":false},{"pmid":"22226966","id":"PMC_22226966","title":"The AAA-ATPase NVL2 is a telomerase component essential for holoenzyme assembly.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22226966","citation_count":29,"is_preprint":false},{"pmid":"9286697","id":"PMC_9286697","title":"NVL: a new member of the AAA family of ATPases localized to the nucleus.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9286697","citation_count":28,"is_preprint":false},{"pmid":"26166824","id":"PMC_26166824","title":"NVL2, a nucleolar AAA-ATPase, is associated with the nuclear exosome and is involved in pre-rRNA processing.","date":"2015","source":"Biochemical and 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signal.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21474449","citation_count":19,"is_preprint":false},{"pmid":"25891250","id":"PMC_25891250","title":"The NVL gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population.","date":"2015","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25891250","citation_count":16,"is_preprint":false},{"pmid":"33422691","id":"PMC_33422691","title":"Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2.","date":"2021","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33422691","citation_count":7,"is_preprint":false},{"pmid":"39706051","id":"PMC_39706051","title":"Pre-ribosomal WDR74 module coordinates the early and late pre-rRNA processing stages for the NVL2-mediated regulation of 60S ribosome biogenesis.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39706051","citation_count":3,"is_preprint":false},{"pmid":"40780730","id":"PMC_40780730","title":"Development of an enzyme-linked immunosorbent assay for the efficient detection of autoantibodies against nuclear valosin-containing protein-like protein (NVL) 2 using its manipulated cDNA.","date":"2025","source":"RMD open","url":"https://pubmed.ncbi.nlm.nih.gov/40780730","citation_count":1,"is_preprint":false},{"pmid":"40714107","id":"PMC_40714107","title":"Prediction of potential drug-resistant ALK mutations against fourth-generation inhibitors NVL-655 and TPX-0131.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40714107","citation_count":1,"is_preprint":false},{"pmid":"40766499","id":"PMC_40766499","title":"A small molecule inhibitor of NVL suppresses tumor growth by blocking ribosome biogenesis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40766499","citation_count":0,"is_preprint":false},{"pmid":"41422678","id":"PMC_41422678","title":"NVL2-interacting protein CWF19L2 is required for debranching of intron-derived lariat RNAs.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41422678","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.26.656085","title":"Preclinical Prediction of Resistance and Optimization of Sequential Therapy for ALK-positive Lung Cancer Using Next-generation ALK Inhibitors","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.656085","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.02.616320","title":"Onco-fetal protein Nogo-A restricts human and mouse glioma vascularization and growth via VEGF-Notch-hippo-metabolic signaling","date":"2024-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.02.616320","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12068,"output_tokens":3451,"usd":0.043985,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11012,"output_tokens":3748,"usd":0.07438,"stage2_stop_reason":"end_turn"},"total_usd":0.118365,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"NVL encodes an ~110-kDa nuclear protein with two highly similar ATP-binding domains, establishing it as a member of the AAA ATPase family localized to the nucleus.\",\n      \"method\": \"Degenerate PCR cloning, cDNA sequencing, nuclear localization confirmed by protein characterization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — initial cloning and nuclear localization by protein characterization, single lab, foundational identification study\",\n      \"pmids\": [\"9286697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NVL2 (the major isoform with a longer N-terminal extension) localizes to the nucleolus, whereas NVL1 is nucleoplasmic. Mutational analysis identified two nuclear localization signals and a distinct nucleolar localization signal (NoLS) within NVL2's N-terminal extra region.\",\n      \"method\": \"Mutational analysis, subcellular fractionation, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutational analysis with multiple mutants, direct imaging, replicated across NVL1 vs NVL2 comparison\",\n      \"pmids\": [\"15469983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NVL2 interacts with ribosomal protein L5 through its nucleolar localization signal; this interaction is ATP-dependent and contributes to nucleolar translocation of NVL2. A dominant-negative NVL2 mutant inhibits ribosome biosynthesis.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, dominant-negative overexpression with ribosome biosynthesis readout\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus functional dominant-negative assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15469983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NVL2 is associated with pre-ribosomal particles in the nucleus and interacts with the DExD/H-box RNA helicase DOB1/MTR4. This interaction requires the first ATP-binding module of NVL2; a dominant-negative second-module mutant causes aberrant retention of DOB1 on pre-ribosomal particles, suggesting NVL2 regulates association/dissociation of DOB1 from these particles.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ATPase domain mutagenesis, cellular overexpression of dominant-negative mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, domain mutagenesis, functional dominant-negative assay in multiple orthogonal methods\",\n      \"pmids\": [\"16782053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The solution structure of the N-terminal unique domain of NVL2 (NVL2-UD) was determined by NMR and found to adopt a winged-helix-like fold distinct from VCP/p97. NVL2-UD binds nucleolin from HeLa extracts in an RNA-dependent manner, with RRKR basic residues in a characteristic loop being necessary and sufficient for nucleolin-RNA complex binding and nucleolar localization.\",\n      \"method\": \"NMR structure determination, binding assays with HeLa cell extracts, mutagenesis of RRKR residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus mutagenesis plus binding assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"21474449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NVL2 interacts with hTERT (human telomerase reverse transcriptase) in the nucleolus and is found in association with catalytically competent telomerase. Depletion of NVL2 by siRNA decreases hTERT protein levels (without affecting hTERT mRNA) and reduces telomerase activity. ATP-binding activity of NVL2 is required for hTERT binding and telomerase assembly.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, siRNA knockdown, TRAP assay for telomerase activity, RT-qPCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockdown with enzymatic activity readout, ATP-binding mutant analysis, single lab with multiple methods\",\n      \"pmids\": [\"22226966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NVL2 is associated with the nuclear exosome complex (including RRP6 as a nucleus-specific catalytic subunit). This interaction is mediated by MTR4 and RRP6, as depletion of either prevents NVL2-exosome association. MPP6 (another exosome cofactor) is also required, as its knockdown causes MTR4 to dissociate from the nuclear exosome. ATPase domain mutations in NVL2 cause defects in pre-rRNA processing into mature 28S and 5.8S rRNAs.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ATPase domain mutagenesis, northern blotting/rRNA processing assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs with knockdowns plus domain mutagenesis plus pre-rRNA processing readout, multiple orthogonal methods\",\n      \"pmids\": [\"26166824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NVL2 acts on the MTR4-exosome complex to stimulate ATP hydrolysis-dependent dissociation of WDR74 (a WD repeat protein with similarity to yeast Nsa1). Knockdown of WDR74 decreases 60S ribosome levels, and WDR74 co-localizes with NVL2 in the nucleolus.\",\n      \"method\": \"Proteomic screen, co-immunoprecipitation, ATPase-deficient NVL2 mutant, siRNA knockdown, ribosome profiling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic screen plus Co-IP with domain mutant plus knockdown and functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"26456651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDR74 knockdown causes defects in pre-rRNA cleavage within ITS1, an early step in the 60S processing pathway. Expression of ATPase-deficient NVL2 also causes the same ITS1 processing defect with partial redistribution of WDR74 from nucleolus to nucleoplasm, where increased WDR74-MTR4 interaction is detected. This establishes that NVL2 ATPase activity spatiotemporally regulates WDR74 dissociation from the MTR4-exosome complex for proper pre-60S maturation.\",\n      \"method\": \"siRNA knockdown, dominant-negative NVL2 overexpression, northern blotting for pre-rRNA processing, in situ proximity ligation assay, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown plus dominant-negative mutant plus proximity ligation assay plus pre-rRNA processing, multiple orthogonal methods\",\n      \"pmids\": [\"29107693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPF30 (a Tudor domain-containing pre-mRNA splicing factor) is an MTR4-interacting protein whose association with the MTR4-exosome complex is regulated by NVL2 ATPase activity, analogous to WDR74. The interaction between SPF30 and the exosome core is mediated by MTR4 and RRP6. Knockdown of SPF30 caused a subtle delay in 12S pre-rRNA processing to mature 5.8S rRNA.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, shotgun proteomics (interactome), rRNA processing assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus shotgun proteomics plus knockdown functional readout, single lab with multiple methods\",\n      \"pmids\": [\"33422691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR74 functions as part of a pre-ribosomal subcomplex (the WDR74 module) consisting of WDR74, RPF1, MAK16, and RRP1. Each component is mutually required for the interaction of the others with MTR4. NVL2 dysfunction (ATP hydrolysis-deficient mutant) prevents MTR4 from recruiting PICT1 (an MTR4 adaptor required for 5.8S rRNA 3'-end maturation) by blocking release of the WDR74 module from the MTR4-exosome complex.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, siRNA knockdown, pre-rRNA processing assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP/MS plus individual knockdowns plus functional pre-rRNA processing readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"39706051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A small molecule inhibitor MM17 (dibenzothiazepinone) binds NVL at two sites on the hexameric assembly as revealed by cryo-EM. Mutations in NVL at these sites confer resistance to MM17. NVL inhibition arrests 60S ribosome biogenesis in the nucleolus and induces cell cycle arrest or apoptosis via MDM2/p53-dependent and p53-independent pathways without causing DNA damage. A bioavailable analog MM927 suppresses tumor growth in mouse leukemia and colorectal cancer models.\",\n      \"method\": \"Forward genetics (resistance mutations), cryo-EM structure of NVL hexamer with inhibitor, in vitro and cellular inhibitor treatment, MDM2/p53 pathway analysis, mouse tumor models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus resistance genetics plus mechanistic pathway dissection plus in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"40766499\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CWF19L2 is a novel NVL2-interacting protein that associates with intron lariat spliceosome (ILS) components, lariat RNA debranching enzyme DBR1, and the MTR4-RNA exosome complex. CWF19L2 is required for debranching of intron-derived lariat RNAs, functioning as potently as DBR1 itself.\",\n      \"method\": \"Co-immunoprecipitation, RNA debranching assay (minigene splicing reporter, RT-PCR for endogenous lariat RNA), super-resolution immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional debranching assay plus imaging, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41422678\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NVL2 is a nucleolar AAA-ATPase that forms hexameric assemblies and functions as a chaperone-like remodeling factor during 60S ribosomal subunit biogenesis: it uses ATP hydrolysis to drive the dissociation of processing factors (WDR74 module, SPF30, DOB1/MTR4) from pre-ribosomal particles and the nuclear exosome complex, thereby coordinating sequential pre-rRNA cleavage and processing steps; it also associates with hTERT to support telomerase holoenzyme assembly, interacts with nucleolin-RNA complexes via its structurally unique N-terminal domain, and its inhibition by small molecules (MM17/MM927) arrests 60S biogenesis and triggers MDM2/p53-dependent apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NVL encodes a nuclear AAA-ATPase whose major isoform, NVL2, is targeted to the nucleolus and operates as an energy-dependent remodeling factor in ribosome biogenesis [#0, #1]. NVL2 associates with pre-ribosomal particles and engages the ribosomal protein L5 and the DExD/H-box helicase MTR4/DOB1 through its ATP-binding modules; ATPase activity drives the controlled release of processing factors from these particles, and ATPase-deficient mutants cause aberrant retention of MTR4 and defective maturation of 28S and 5.8S rRNAs [#2, #3, #6]. Acting on the MTR4-nuclear exosome complex, NVL2 stimulates ATP hydrolysis-dependent dissociation of a WDR74 module (WDR74-RPF1-MAK16-RRP1) and of the splicing factor SPF30, thereby controlling early ITS1 cleavage and licensing recruitment of the adaptor PICT1 for 5.8S 3'-end maturation during 60S subunit assembly [#7, #8, #9, #10]. A structurally distinct N-terminal winged-helix domain anchors NVL2 to the nucleolus by binding nucleolin-RNA complexes via an RRKR loop, and NVL2 additionally associates with hTERT to support telomerase holoenzyme assembly and activity [#4, #5]. Small-molecule inhibition of the NVL hexamer arrests nucleolar 60S biogenesis and triggers MDM2/p53-dependent and p53-independent cell-cycle arrest or apoptosis [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the gene product's basic identity—an unknown nuclear protein was defined as a two-domain AAA-ATPase, framing all subsequent mechanistic work around ATP-driven remodeling.\",\n      \"evidence\": \"Degenerate PCR cloning, cDNA sequencing and nuclear localization by protein characterization\",\n      \"pmids\": [\"9286697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate or pathway assigned\", \"No subnuclear resolution beyond bulk nuclear localization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved why NVL has two functional forms and connected it to ribosome production—NVL2's N-terminal extension carries a nucleolar localization signal and mediates ATP-dependent binding to ribosomal protein L5, with a dominant-negative mutant blocking ribosome biosynthesis.\",\n      \"evidence\": \"Mutational analysis, subcellular fractionation, fluorescence microscopy, yeast two-hybrid and Co-IP with dominant-negative ribosome readout\",\n      \"pmids\": [\"15469983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step of ribosome biogenesis affected not defined\", \"Biochemical role of ATP hydrolysis vs binding unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the first direct enzymatic substrate-like partner—NVL2 binds MTR4/DOB1 via its first ATP module, and a second-module mutant traps DOB1 on pre-ribosomal particles, establishing NVL2 as a regulator of factor association/dissociation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, ATPase domain mutagenesis, dominant-negative overexpression\",\n      \"pmids\": [\"16782053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ATP-driven remodeling not reconstituted in vitro\", \"Distinct roles of the two ATP modules not fully separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the structural basis of nucleolar targeting and revealed a second functional axis—an NMR structure showed a unique winged-helix N-terminal domain whose RRKR loop binds nucleolin-RNA complexes, while a separate study linked NVL2 to hTERT and telomerase assembly.\",\n      \"evidence\": \"NMR structure determination, RRKR mutagenesis, HeLa extract binding assays; Co-IP, siRNA knockdown and TRAP telomerase activity assay\",\n      \"pmids\": [\"21474449\", \"22226966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between nucleolin binding and ribosome remodeling unclear\", \"How NVL2 promotes hTERT stability/telomerase assembly mechanistically undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed NVL2 within the nuclear exosome machinery and tied its ATPase to rRNA maturation—NVL2 joins the MTR4-exosome (RRP6, MPP6) and, via ATP hydrolysis, drives dissociation of the 60S factor WDR74, with ATPase mutants causing 28S/5.8S processing defects.\",\n      \"evidence\": \"Co-IP with knockdowns of MTR4/RRP6/MPP6, ATPase domain mutagenesis, northern blotting, proteomic screen and ribosome profiling\",\n      \"pmids\": [\"26166824\", \"26456651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of WDR74 release relative to other steps not defined\", \"In vitro reconstitution of ATP-driven dissociation absent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided spatiotemporal mechanism—NVL2 ATPase activity controls where and when WDR74 detaches from the MTR4-exosome, with ATPase-deficient NVL2 redistributing WDR74 to the nucleoplasm and blocking ITS1 cleavage, an early 60S step.\",\n      \"evidence\": \"siRNA knockdown, dominant-negative NVL2, northern blotting, in situ proximity ligation assay, immunofluorescence\",\n      \"pmids\": [\"29107693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream consequences of mislocalized WDR74 on later maturation not traced\", \"Coupling between cleavage and factor release mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the remodeling model to additional clients—SPF30 was shown to be an MTR4-exosome-associated factor whose release is NVL2 ATPase-regulated like WDR74, with knockdown delaying 12S-to-5.8S processing.\",\n      \"evidence\": \"Co-IP, shotgun proteomics, siRNA knockdown, rRNA processing assay\",\n      \"pmids\": [\"33422691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of subtle processing delay unclear\", \"Direct ATP-dependence of SPF30 release not shown by mutant in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the substrate as a multiprotein module and its downstream coupling—WDR74 acts within a WDR74-RPF1-MAK16-RRP1 subcomplex, and NVL2 ATPase failure blocks module release and prevents MTR4 from recruiting the PICT1 adaptor needed for 5.8S 3'-end maturation.\",\n      \"evidence\": \"Co-IP/mass spectrometry, individual siRNA knockdowns, pre-rRNA processing assays\",\n      \"pmids\": [\"39706051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of module recognition by NVL2 unknown\", \"Whether NVL2 directly contacts PICT1 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Delivered structural and therapeutic validation—a cryo-EM structure of the NVL hexamer bound to inhibitor MM17 (confirmed by resistance mutations) showed that blocking NVL arrests nucleolar 60S biogenesis and induces MDM2/p53-dependent and -independent death, with an analog suppressing tumors in vivo; CWF19L2 was identified as a new NVL2 partner linking it to lariat RNA debranching.\",\n      \"evidence\": \"Cryo-EM, forward-genetics resistance mutations, cellular and mouse tumor models, p53 pathway analysis (preprint); Co-IP, RNA debranching assays, super-resolution imaging\",\n      \"pmids\": [\"40766499\", \"41422678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MM17/MM927 results are from a preprint pending peer review\", \"Mechanistic role of CWF19L2-NVL2 association in debranching vs ribosome biogenesis not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NVL2 ATP hydrolysis is mechanically coupled to client release on pre-ribosomal particles, and whether its ribosome-biogenesis and telomerase roles are mechanistically linked, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vitro reconstitution of ATP-driven factor dissociation\", \"Structural basis for substrate engagement by the hexamer incompletely defined\", \"Relationship between nucleolin/hTERT binding and 60S remodeling unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3, 6, 7, 8, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 8, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 2, 4, 5, 7, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 6, 7, 8, 10]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"MTR4-nuclear exosome complex\",\n      \"WDR74 module (WDR74-RPF1-MAK16-RRP1)\",\n      \"telomerase holoenzyme\"\n    ],\n    \"partners\": [\n      \"MTR4\",\n      \"RRP6\",\n      \"MPP6\",\n      \"WDR74\",\n      \"SPF30\",\n      \"hTERT\",\n      \"RPL5\",\n      \"CWF19L2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}