{"gene":"GNL3","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2006,"finding":"Yeast Nug1 (ortholog of GNL3) contains an N-terminal RNA-binding domain that is sufficient and necessary for nucleolar/nuclear targeting and association with pre-60S ribosomal particles; the middle circularly permuted GTPase domain has intrinsic GTP hydrolysis activity in vitro but is not essential for cell growth; the C-terminal domain is essential for ribosome biogenesis.","method":"Domain deletion analysis, in vitro GTPase assay, genetic epistasis with pre-60S factors Noc2, Noc3, and Dbp10","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay combined with multiple domain mutants, genetic epistasis, and RNA-binding activity demonstrated in a single focused study","pmids":["16803892"],"is_preprint":false},{"year":2016,"finding":"Yeast Nug1/GNL3 exhibits low intrinsic GTPase activity that is stimulated by potassium ions (K⁺-dependent GTPase). Nug1 physically interacts with the RNA helicase Dbp10, and this interaction was reconstituted in vitro using Chaetomium thermophilum orthologs. In vivo rRNA-protein crosslinking showed Nug1 and Dbp10 bind at proximal and partially overlapping sites on the pre-60S ribosome, prominently at helix H89 that forms part of the peptidyl transferase center (PTC). Depletion of Nug1 or expression of a nucleotide-binding mutant causes loss of Dbp10 from early pre-60S particles.","method":"In vitro enzymatic GTPase assay, in vitro reconstitution of Nug1-Dbp10 interaction, in vivo rRNA-protein crosslinking, depletion and nucleotide-binding mutant analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, enzymatic assay, and in vivo crosslinking with mutant validation, multiple orthogonal methods","pmids":["26823502"],"is_preprint":false},{"year":2016,"finding":"GNL3/nucleostemin (NS) promotes nucleolar polyubiquitylation of the CDK inhibitor p27kip1 in hepatocellular carcinoma cells; subcellular fractionation showed nucleolar p27 has significantly higher polyubiquitylation than nucleoplasmic p27; depletion of NS inhibited nucleolar polyubiquitylation of p27, leading to increased binding of p27 to CDK2-Cyclin E complex and CDK2 inhibition with consequent cell cycle arrest.","method":"Subcellular fractionation, co-immunoprecipitation of p27 with NS, ubiquitylation assay, CDK2 activity assay, siRNA knockdown","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and fractionation with functional readout (CDK2 activity, cell cycle), single lab with two orthogonal methods","pmids":["27998760"],"is_preprint":false},{"year":2019,"finding":"XBP1 transcription factor binds to the GNL3 promoter (demonstrated by dual-luciferase reporter assay) and activates GNL3 expression; XBP1 overexpression rescues the inhibitory effects on proliferation, invasion, and EMT caused by GNL3 knockdown in osteosarcoma cells, placing GNL3 downstream of XBP1.","method":"Dual-luciferase reporter assay, siRNA knockdown, overexpression rescue experiment","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay establishing direct transcriptional regulation plus epistasis rescue, single lab","pmids":["30936750"],"is_preprint":false},{"year":2023,"finding":"Human GNL3/nucleostemin prevents nuclease-dependent resection of nascent DNA at stalled replication forks by limiting origin firing; GNL3 interacts with the DNA replication initiation factor ORC2 in the nucleolus, and GNL3 depletion causes excess origin firing and exhaustion of available RPA, driving DNA resection. GNL3 concentration in the nucleolus is required to sequester ORC2 and limit replication stress-induced DNA resection.","method":"DNA fiber assay (nascent DNA resection), co-immunoprecipitation of GNL3 and ORC2, live-cell imaging/fractionation showing nucleolar localization, inhibition of origin firing rescue experiment","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction established, functional rescue by inhibiting origin firing, nucleolar localization linked directly to resection phenotype, multiple orthogonal methods","pmids":["37965896"],"is_preprint":false},{"year":2021,"finding":"GNL3 knockdown in HeLa cells down-regulates expression of IL24 and PTN as determined by RNA-seq; this was validated in the chondrosarcoma cell line SW1353, positioning GNL3 as an upstream regulator of IL24 and PTN transcription.","method":"RNA-seq after shRNA-mediated GNL3 knockdown, validated by qRT-PCR in SW1353 cells","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomics with validation but no direct mechanistic experiment linking GNL3 to the promoters of IL24/PTN, single lab","pmids":["33358901"],"is_preprint":false},{"year":2025,"finding":"GNL3 undergoes SUMOylation at K196, mediated by the nucleolar deubiquitinating enzyme USP36 acting as a SUMO ligase, and deSUMOylated by SENP3. SUMOylated GNL3 interacts with the BLM-DNA2 helicase-nuclease complex via SUMO-interacting motifs (SIMs) in both proteins, promoting DNA end resection, RPA loading, and RAD51 loading for homologous recombination (HR) repair. A SUMO-defective K196R mutant fails to rescue DNA damage response induced by endogenous GNL3 knockdown. Several breast cancer-derived GNL3 variants that disrupt SUMOylation or SIM fail to interact with BLM-DNA2.","method":"SUMOylation assay with wild-type and K196R mutant, co-immunoprecipitation of GNL3 with BLM-DNA2, DNA end resection assay, RPA/RAD51 loading assay, SENP3 and USP36 functional experiments, breast cancer variant analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including mutagenesis, co-IP, and functional assays, but preprint with no peer review yet","pmids":["41279596"],"is_preprint":true},{"year":2026,"finding":"GNL3 physically interacts with the androgen receptor (AR), enhances AR chromatin occupancy, and coactivates transcription of proliferation genes NEK2 and CDC20 in castration-resistant prostate cancer (CRPC). Concurrently, GNL3 functions as a corepressor of immune-responsive genes (CXCL10, TAP1) via class I HDACs, enabling CD8+ T cell elimination and immunosuppressive tumor microenvironment. AR-GNL3 complex formation increases from primary PCa to CRPC.","method":"Proteomic profiling, co-immunoprecipitation of GNL3 with AR, chromatin occupancy assay, transcriptional reporter assays, GNL3 knockdown in CRPC cells with functional readouts (proliferation, metastasis, CD8+ T cell assay)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing physical interaction, chromatin occupancy, and two orthogonal functional readouts (transcriptional coactivation and corepression), single lab","pmids":["41772945"],"is_preprint":false},{"year":2026,"finding":"Nuclear ENO2 binds GNL3 lactylated at Lys-5 (mediated by ENO2 Glu-4 residue), displacing MDM2 from GNL3. This results in MDM2 destabilization, impaired p53 ubiquitination, p53 accumulation, and chondrocyte senescence. p53 in turn transcriptionally activates ENO2, forming a positive feedback loop. Pharmacological inhibition of ENO2 restores p53 degradation and mitigates OA in aged mice.","method":"Co-immunoprecipitation, GST pull-down, site-directed mutagenesis (E4A-ENO2 and K5R-GNL3 mutants), lactylomics, in vivo mouse OA model with intra-articular ENO2 inhibitor injection","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution by GST pull-down, validated with site-directed mutagenesis of interaction residues, Co-IP, in vivo model; multiple orthogonal methods in one study","pmids":["42192505"],"is_preprint":false},{"year":2022,"finding":"GNL3 regulates SIRT1 expression in hepatocellular carcinoma cells, and mediates stem cell-like properties of HCC cells through SIRT1; silencing GNL3 inhibits proliferation, migration, and invasion of HCC cells in vitro and reduces tumor growth in vivo.","method":"siRNA knockdown of GNL3, Western blot for SIRT1, CCK-8 and Transwell assays, subcutaneous tumor-bearing animal model","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with expression readout for SIRT1 but no direct mechanistic link (e.g., ChIP, reporter assay) between GNL3 and SIRT1 transcription established in abstract; single lab, single method","pmids":["35432540"],"is_preprint":false}],"current_model":"GNL3/nucleostemin is a nucleolar GTP-binding protein that functions in at least three mechanistically distinct processes: (1) ribosome biogenesis, where its N-terminal RNA-binding domain mediates association with pre-60S particles and its K⁺-stimulated GTPase activity facilitates recruitment of the Dbp10 helicase to the nascent peptidyl transferase center; (2) genome integrity, where SUMOylation at K196 (written by USP36, erased by SENP3) enables interaction with the BLM-DNA2 complex to promote homologous recombination–mediated DNA end resection, while its nucleolar sequestration of ORC2 limits excess origin firing and replication stress–induced resection; and (3) cell cycle and oncogenic signaling, where it promotes nucleolar polyubiquitylation and inactivation of p27kip1, acts as a dual coregulator of androgen receptor transcription (coactivating proliferation genes via direct AR interaction and corepressing immune genes via class I HDACs), and is regulated upstream by XBP1 and ENO2-mediated lactylation that disrupts a GNL3–MDM2–p53 axis."},"narrative":{"mechanistic_narrative":"GNL3 (nucleostemin) is a nucleolar GTP-binding protein that operates across ribosome biogenesis, genome integrity, and cell-cycle/oncogenic signaling [PMID:16803892, PMID:37965896, PMID:41772945]. In ribosome biogenesis, work on the yeast ortholog Nug1 established a modular architecture in which an N-terminal RNA-binding domain mediates nucleolar targeting and association with pre-60S particles, a circularly permuted GTPase domain hydrolyzes GTP, and the C-terminal domain is essential for biogenesis [PMID:16803892]; this GTPase activity is stimulated by potassium, and Nug1 binds the RNA helicase Dbp10 at overlapping sites near helix H89 of the nascent peptidyl transferase center, with Nug1 depletion or nucleotide-binding mutation causing loss of Dbp10 from early pre-60S particles [PMID:26823502]. In genome maintenance, GNL3 sequesters the replication initiation factor ORC2 in the nucleolus to limit origin firing and prevent RPA exhaustion and nuclease-dependent resection of stalled forks [PMID:37965896], whereas SUMOylation at K196 (written by USP36, erased by SENP3) licenses GNL3 to engage the BLM-DNA2 helicase-nuclease complex through SUMO-interacting motifs and promote end resection, RPA and RAD51 loading during homologous recombination [PMID:41279596]. In cancer signaling, GNL3 promotes nucleolar polyubiquitylation and inactivation of the CDK inhibitor p27kip1, releasing CDK2-Cyclin E activity [PMID:27998760], and acts as a dual coregulator of the androgen receptor, coactivating proliferation genes NEK2 and CDC20 while corepressing immune genes CXCL10 and TAP1 via class I HDACs in castration-resistant prostate cancer [PMID:41772945]. GNL3 is itself a node in a p53 axis: lactylation at Lys-5 promotes binding by nuclear ENO2, which displaces MDM2 from GNL3, stabilizing p53 and driving chondrocyte senescence [PMID:42192505], and its expression is transcriptionally activated by XBP1 [PMID:30936750].","teleology":[{"year":2006,"claim":"Established the domain logic of the GNL3 ortholog, defining which regions confer nucleolar targeting, GTP hydrolysis, and essentiality in ribosome biogenesis.","evidence":"Domain deletion analysis, in vitro GTPase assay, and genetic epistasis with pre-60S factors in yeast Nug1","pmids":["16803892"],"confidence":"High","gaps":["Did not identify the substrate/effector of the GTPase activity","Human GNL3 architecture inferred from yeast ortholog"]},{"year":2016,"claim":"Resolved how the GTPase couples to ribosome assembly, showing K⁺-stimulated GTPase activity and direct binding to the Dbp10 helicase at the peptidyl transferase center.","evidence":"In vitro reconstitution of Nug1-Dbp10 interaction, enzymatic GTPase assay, and in vivo rRNA-protein crosslinking with mutant validation","pmids":["26823502"],"confidence":"High","gaps":["Mechanism by which GTP hydrolysis triggers Dbp10 release not defined","Conservation of the K⁺-stimulation in human GNL3 not tested here"]},{"year":2016,"claim":"Connected GNL3 to cell-cycle control by showing it drives nucleolar polyubiquitylation that inactivates the CDK inhibitor p27kip1.","evidence":"Subcellular fractionation, reciprocal co-IP of p27 with NS, ubiquitylation and CDK2 activity assays with siRNA knockdown in hepatocellular carcinoma cells","pmids":["27998760"],"confidence":"Medium","gaps":["E3 ligase responsible for p27 ubiquitylation not identified","Whether GTPase activity is required for this function untested"]},{"year":2019,"claim":"Placed GNL3 downstream of a transcriptional regulator by showing XBP1 binds the GNL3 promoter and that GNL3 is required for XBP1-driven proliferation and invasion.","evidence":"Dual-luciferase reporter assay, siRNA knockdown, and overexpression rescue in osteosarcoma cells","pmids":["30936750"],"confidence":"Medium","gaps":["Downstream effectors of GNL3 in the XBP1 axis not defined","Single cell-context"]},{"year":2022,"claim":"Linked GNL3 to stem-like tumor properties through SIRT1, though without a direct regulatory mechanism.","evidence":"siRNA knockdown with SIRT1 Western blot, proliferation/invasion assays, and a subcutaneous xenograft model","pmids":["35432540"],"confidence":"Low","gaps":["No direct mechanistic link (ChIP/reporter) between GNL3 and SIRT1 transcription","Single lab, single readout"]},{"year":2023,"claim":"Defined a genome-protective role in which GNL3 sequesters ORC2 to restrain origin firing and prevent RPA exhaustion and fork resection.","evidence":"DNA fiber resection assay, reciprocal GNL3-ORC2 co-IP, nucleolar fractionation, and origin-firing inhibition rescue","pmids":["37965896"],"confidence":"High","gaps":["How GNL3 nucleolar concentration is dynamically regulated during replication stress unclear","Structural basis of GNL3-ORC2 binding unknown"]},{"year":2025,"claim":"Showed that SUMOylation of GNL3 at K196 is the switch that recruits the BLM-DNA2 complex to drive homologous-recombination end resection.","evidence":"SUMOylation assays with K196R mutant, co-IP of GNL3 with BLM-DNA2, RPA/RAD51 loading assays, SENP3/USP36 manipulation, and breast cancer variant analysis (preprint)","pmids":["41279596"],"confidence":"Medium","gaps":["Preprint, not yet peer reviewed","Apparent opposite effect on resection versus the ORC2 pathway not reconciled","Functional impact of breast cancer variants in vivo untested"]},{"year":2026,"claim":"Established GNL3 as a dual transcriptional coregulator of the androgen receptor, simultaneously activating proliferation genes and repressing immune genes in castration-resistant prostate cancer.","evidence":"Proteomic profiling, reciprocal GNL3-AR co-IP, chromatin occupancy and reporter assays, knockdown with proliferation/metastasis/CD8+ T cell readouts","pmids":["41772945"],"confidence":"Medium","gaps":["Whether GTPase or nucleolar functions are required for AR coregulation unknown","Direct corepressor recruitment mechanism at immune gene loci not fully defined"]},{"year":2026,"claim":"Defined GNL3 as a p53-regulatory node in which Lys-5 lactylation recruits ENO2 to displace MDM2, stabilizing p53 and driving chondrocyte senescence.","evidence":"Co-IP, GST pull-down, site-directed mutagenesis (E4A-ENO2, K5R-GNL3), lactylomics, and an in vivo mouse osteoarthritis model with ENO2 inhibitor","pmids":["42192505"],"confidence":"High","gaps":["How GNL3-MDM2 binding is coupled to MDM2 destabilization mechanistically unclear","Relevance of the lactylation axis outside chondrocytes untested"]},{"year":null,"claim":"It remains unresolved how GNL3's conserved nucleolar GTPase/ribosome-biogenesis activity mechanistically connects to its diverse roles in DNA replication, HR repair, p27/p53 regulation, and AR transcription.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying the GTPase domain with the genome-integrity and transcriptional functions","Whether nucleotide binding is required for the non-ribosomal functions untested","Apparent opposing roles in limiting versus promoting resection unreconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,2]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]}],"complexes":[],"partners":["DBP10","ORC2","BLM","DNA2","USP36","SENP3","AR","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVP2","full_name":"Guanine nucleotide-binding protein-like 3","aliases":["E2-induced gene 3 protein","Novel nucleolar protein 47","NNP47","Nucleolar GTP-binding protein 3","Nucleostemin"],"length_aa":549,"mass_kda":62.0,"function":"May be required to maintain the proliferative capacity of stem cells. Stabilizes MDM2 by preventing its ubiquitination, and hence proteasomal degradation (By similarity)","subcellular_location":"Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9BVP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GNL3","classification":"Common Essential","n_dependent_lines":1155,"n_total_lines":1208,"dependency_fraction":0.9561258278145696},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163938","cell_line_id":"CID001043","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"ARGLU1","stoichiometry":10.0},{"gene":"RBMX2","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"SRSF6","stoichiometry":10.0},{"gene":"CHERP","stoichiometry":10.0},{"gene":"SUB1","stoichiometry":10.0},{"gene":"U2SURP","stoichiometry":10.0},{"gene":"SEC61B","stoichiometry":10.0},{"gene":"CTCF","stoichiometry":4.0},{"gene":"SSRP1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001043","total_profiled":1310},"omim":[{"mim_id":"617103","title":"ZINC FINGER PROTEIN 668; ZNF668","url":"https://www.omim.org/entry/617103"},{"mim_id":"608011","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN-LIKE 3; GNL3","url":"https://www.omim.org/entry/608011"},{"mim_id":"300873","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN-LIKE 3-LIKE PROTEIN; GNL3L","url":"https://www.omim.org/entry/300873"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GNL3"},"hgnc":{"alias_symbol":["C77032","E2IG3","MGC800","NS","Nug1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BVP2","domains":[{"cath_id":"3.40.50.300","chopping":"127-209_232-313_406-463","consensus_level":"high","plddt":90.4722,"start":127,"end":463},{"cath_id":"1.10.1580","chopping":"318-403","consensus_level":"medium","plddt":88.9099,"start":318,"end":403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVP2-F1-predicted_aligned_error_v6.png","plddt_mean":75.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNL3","jax_strain_url":"https://www.jax.org/strain/search?query=GNL3"},"sequence":{"accession":"Q9BVP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVP2"}},"corpus_meta":[{"pmid":"16803892","id":"PMC_16803892","title":"The NUG1 GTPase reveals and N-terminal RNA-binding domain that is essential for association with 60 S pre-ribosomal particles.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16803892","citation_count":51,"is_preprint":false},{"pmid":"12441390","id":"PMC_12441390","title":"Crystal structures and increased stabilization of the protein G variants with switched folding pathways NuG1 and NuG2.","date":"2002","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/12441390","citation_count":49,"is_preprint":false},{"pmid":"26429724","id":"PMC_26429724","title":"GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes.","date":"2015","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/26429724","citation_count":44,"is_preprint":false},{"pmid":"28849076","id":"PMC_28849076","title":"Upregulation of GNL3 expression promotes colon cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28849076","citation_count":37,"is_preprint":false},{"pmid":"26823502","id":"PMC_26823502","title":"The K⁺-dependent GTPase Nug1 is implicated in the association of the helicase Dbp10 to the immature peptidyl transferase centre during ribosome maturation.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26823502","citation_count":35,"is_preprint":false},{"pmid":"24886551","id":"PMC_24886551","title":"Allelic expression analysis of the osteoarthritis susceptibility locus that maps to chromosome 3p21 reveals cis-acting eQTLs at GNL3 and SPCS1.","date":"2014","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24886551","citation_count":25,"is_preprint":false},{"pmid":"32826963","id":"PMC_32826963","title":"Integrative analyses prioritize GNL3 as a risk gene for bipolar disorder.","date":"2020","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32826963","citation_count":21,"is_preprint":false},{"pmid":"27998760","id":"PMC_27998760","title":"Nucleostemin/GNL3 promotes nucleolar polyubiquitylation of p27kip1 to drive hepatocellular carcinoma progression.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27998760","citation_count":18,"is_preprint":false},{"pmid":"33358901","id":"PMC_33358901","title":"RNA binding protein GNL3 up-regulates IL24 and PTN to promote the development of osteoarthritis.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33358901","citation_count":15,"is_preprint":false},{"pmid":"30936750","id":"PMC_30936750","title":"The oncogenic role of GNL3 in the progression and metastasis of osteosarcoma.","date":"2019","source":"Cancer management and 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/42192505","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12776,"output_tokens":3195,"usd":0.043126,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10608,"output_tokens":3601,"usd":0.071532,"stage2_stop_reason":"end_turn"},"total_usd":0.114658,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Nug1 (ortholog of GNL3) contains an N-terminal RNA-binding domain that is sufficient and necessary for nucleolar/nuclear targeting and association with pre-60S ribosomal particles; the middle circularly permuted GTPase domain has intrinsic GTP hydrolysis activity in vitro but is not essential for cell growth; the C-terminal domain is essential for ribosome biogenesis.\",\n      \"method\": \"Domain deletion analysis, in vitro GTPase assay, genetic epistasis with pre-60S factors Noc2, Noc3, and Dbp10\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay combined with multiple domain mutants, genetic epistasis, and RNA-binding activity demonstrated in a single focused study\",\n      \"pmids\": [\"16803892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Yeast Nug1/GNL3 exhibits low intrinsic GTPase activity that is stimulated by potassium ions (K⁺-dependent GTPase). Nug1 physically interacts with the RNA helicase Dbp10, and this interaction was reconstituted in vitro using Chaetomium thermophilum orthologs. In vivo rRNA-protein crosslinking showed Nug1 and Dbp10 bind at proximal and partially overlapping sites on the pre-60S ribosome, prominently at helix H89 that forms part of the peptidyl transferase center (PTC). Depletion of Nug1 or expression of a nucleotide-binding mutant causes loss of Dbp10 from early pre-60S particles.\",\n      \"method\": \"In vitro enzymatic GTPase assay, in vitro reconstitution of Nug1-Dbp10 interaction, in vivo rRNA-protein crosslinking, depletion and nucleotide-binding mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, enzymatic assay, and in vivo crosslinking with mutant validation, multiple orthogonal methods\",\n      \"pmids\": [\"26823502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GNL3/nucleostemin (NS) promotes nucleolar polyubiquitylation of the CDK inhibitor p27kip1 in hepatocellular carcinoma cells; subcellular fractionation showed nucleolar p27 has significantly higher polyubiquitylation than nucleoplasmic p27; depletion of NS inhibited nucleolar polyubiquitylation of p27, leading to increased binding of p27 to CDK2-Cyclin E complex and CDK2 inhibition with consequent cell cycle arrest.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation of p27 with NS, ubiquitylation assay, CDK2 activity assay, siRNA knockdown\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and fractionation with functional readout (CDK2 activity, cell cycle), single lab with two orthogonal methods\",\n      \"pmids\": [\"27998760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"XBP1 transcription factor binds to the GNL3 promoter (demonstrated by dual-luciferase reporter assay) and activates GNL3 expression; XBP1 overexpression rescues the inhibitory effects on proliferation, invasion, and EMT caused by GNL3 knockdown in osteosarcoma cells, placing GNL3 downstream of XBP1.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, overexpression rescue experiment\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay establishing direct transcriptional regulation plus epistasis rescue, single lab\",\n      \"pmids\": [\"30936750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human GNL3/nucleostemin prevents nuclease-dependent resection of nascent DNA at stalled replication forks by limiting origin firing; GNL3 interacts with the DNA replication initiation factor ORC2 in the nucleolus, and GNL3 depletion causes excess origin firing and exhaustion of available RPA, driving DNA resection. GNL3 concentration in the nucleolus is required to sequester ORC2 and limit replication stress-induced DNA resection.\",\n      \"method\": \"DNA fiber assay (nascent DNA resection), co-immunoprecipitation of GNL3 and ORC2, live-cell imaging/fractionation showing nucleolar localization, inhibition of origin firing rescue experiment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction established, functional rescue by inhibiting origin firing, nucleolar localization linked directly to resection phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"37965896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNL3 knockdown in HeLa cells down-regulates expression of IL24 and PTN as determined by RNA-seq; this was validated in the chondrosarcoma cell line SW1353, positioning GNL3 as an upstream regulator of IL24 and PTN transcription.\",\n      \"method\": \"RNA-seq after shRNA-mediated GNL3 knockdown, validated by qRT-PCR in SW1353 cells\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomics with validation but no direct mechanistic experiment linking GNL3 to the promoters of IL24/PTN, single lab\",\n      \"pmids\": [\"33358901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GNL3 undergoes SUMOylation at K196, mediated by the nucleolar deubiquitinating enzyme USP36 acting as a SUMO ligase, and deSUMOylated by SENP3. SUMOylated GNL3 interacts with the BLM-DNA2 helicase-nuclease complex via SUMO-interacting motifs (SIMs) in both proteins, promoting DNA end resection, RPA loading, and RAD51 loading for homologous recombination (HR) repair. A SUMO-defective K196R mutant fails to rescue DNA damage response induced by endogenous GNL3 knockdown. Several breast cancer-derived GNL3 variants that disrupt SUMOylation or SIM fail to interact with BLM-DNA2.\",\n      \"method\": \"SUMOylation assay with wild-type and K196R mutant, co-immunoprecipitation of GNL3 with BLM-DNA2, DNA end resection assay, RPA/RAD51 loading assay, SENP3 and USP36 functional experiments, breast cancer variant analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including mutagenesis, co-IP, and functional assays, but preprint with no peer review yet\",\n      \"pmids\": [\"41279596\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GNL3 physically interacts with the androgen receptor (AR), enhances AR chromatin occupancy, and coactivates transcription of proliferation genes NEK2 and CDC20 in castration-resistant prostate cancer (CRPC). Concurrently, GNL3 functions as a corepressor of immune-responsive genes (CXCL10, TAP1) via class I HDACs, enabling CD8+ T cell elimination and immunosuppressive tumor microenvironment. AR-GNL3 complex formation increases from primary PCa to CRPC.\",\n      \"method\": \"Proteomic profiling, co-immunoprecipitation of GNL3 with AR, chromatin occupancy assay, transcriptional reporter assays, GNL3 knockdown in CRPC cells with functional readouts (proliferation, metastasis, CD8+ T cell assay)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing physical interaction, chromatin occupancy, and two orthogonal functional readouts (transcriptional coactivation and corepression), single lab\",\n      \"pmids\": [\"41772945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Nuclear ENO2 binds GNL3 lactylated at Lys-5 (mediated by ENO2 Glu-4 residue), displacing MDM2 from GNL3. This results in MDM2 destabilization, impaired p53 ubiquitination, p53 accumulation, and chondrocyte senescence. p53 in turn transcriptionally activates ENO2, forming a positive feedback loop. Pharmacological inhibition of ENO2 restores p53 degradation and mitigates OA in aged mice.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, site-directed mutagenesis (E4A-ENO2 and K5R-GNL3 mutants), lactylomics, in vivo mouse OA model with intra-articular ENO2 inhibitor injection\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution by GST pull-down, validated with site-directed mutagenesis of interaction residues, Co-IP, in vivo model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"42192505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GNL3 regulates SIRT1 expression in hepatocellular carcinoma cells, and mediates stem cell-like properties of HCC cells through SIRT1; silencing GNL3 inhibits proliferation, migration, and invasion of HCC cells in vitro and reduces tumor growth in vivo.\",\n      \"method\": \"siRNA knockdown of GNL3, Western blot for SIRT1, CCK-8 and Transwell assays, subcutaneous tumor-bearing animal model\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with expression readout for SIRT1 but no direct mechanistic link (e.g., ChIP, reporter assay) between GNL3 and SIRT1 transcription established in abstract; single lab, single method\",\n      \"pmids\": [\"35432540\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNL3/nucleostemin is a nucleolar GTP-binding protein that functions in at least three mechanistically distinct processes: (1) ribosome biogenesis, where its N-terminal RNA-binding domain mediates association with pre-60S particles and its K⁺-stimulated GTPase activity facilitates recruitment of the Dbp10 helicase to the nascent peptidyl transferase center; (2) genome integrity, where SUMOylation at K196 (written by USP36, erased by SENP3) enables interaction with the BLM-DNA2 complex to promote homologous recombination–mediated DNA end resection, while its nucleolar sequestration of ORC2 limits excess origin firing and replication stress–induced resection; and (3) cell cycle and oncogenic signaling, where it promotes nucleolar polyubiquitylation and inactivation of p27kip1, acts as a dual coregulator of androgen receptor transcription (coactivating proliferation genes via direct AR interaction and corepressing immune genes via class I HDACs), and is regulated upstream by XBP1 and ENO2-mediated lactylation that disrupts a GNL3–MDM2–p53 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNL3 (nucleostemin) is a nucleolar GTP-binding protein that operates across ribosome biogenesis, genome integrity, and cell-cycle/oncogenic signaling [#0, #4, #7]. In ribosome biogenesis, work on the yeast ortholog Nug1 established a modular architecture in which an N-terminal RNA-binding domain mediates nucleolar targeting and association with pre-60S particles, a circularly permuted GTPase domain hydrolyzes GTP, and the C-terminal domain is essential for biogenesis [#0]; this GTPase activity is stimulated by potassium, and Nug1 binds the RNA helicase Dbp10 at overlapping sites near helix H89 of the nascent peptidyl transferase center, with Nug1 depletion or nucleotide-binding mutation causing loss of Dbp10 from early pre-60S particles [#1]. In genome maintenance, GNL3 sequesters the replication initiation factor ORC2 in the nucleolus to limit origin firing and prevent RPA exhaustion and nuclease-dependent resection of stalled forks [#4], whereas SUMOylation at K196 (written by USP36, erased by SENP3) licenses GNL3 to engage the BLM-DNA2 helicase-nuclease complex through SUMO-interacting motifs and promote end resection, RPA and RAD51 loading during homologous recombination [#6]. In cancer signaling, GNL3 promotes nucleolar polyubiquitylation and inactivation of the CDK inhibitor p27kip1, releasing CDK2-Cyclin E activity [#2], and acts as a dual coregulator of the androgen receptor, coactivating proliferation genes NEK2 and CDC20 while corepressing immune genes CXCL10 and TAP1 via class I HDACs in castration-resistant prostate cancer [#7]. GNL3 is itself a node in a p53 axis: lactylation at Lys-5 promotes binding by nuclear ENO2, which displaces MDM2 from GNL3, stabilizing p53 and driving chondrocyte senescence [#8], and its expression is transcriptionally activated by XBP1 [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the domain logic of the GNL3 ortholog, defining which regions confer nucleolar targeting, GTP hydrolysis, and essentiality in ribosome biogenesis.\",\n      \"evidence\": \"Domain deletion analysis, in vitro GTPase assay, and genetic epistasis with pre-60S factors in yeast Nug1\",\n      \"pmids\": [\"16803892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the substrate/effector of the GTPase activity\", \"Human GNL3 architecture inferred from yeast ortholog\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how the GTPase couples to ribosome assembly, showing K\\u207a-stimulated GTPase activity and direct binding to the Dbp10 helicase at the peptidyl transferase center.\",\n      \"evidence\": \"In vitro reconstitution of Nug1-Dbp10 interaction, enzymatic GTPase assay, and in vivo rRNA-protein crosslinking with mutant validation\",\n      \"pmids\": [\"26823502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which GTP hydrolysis triggers Dbp10 release not defined\", \"Conservation of the K\\u207a-stimulation in human GNL3 not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected GNL3 to cell-cycle control by showing it drives nucleolar polyubiquitylation that inactivates the CDK inhibitor p27kip1.\",\n      \"evidence\": \"Subcellular fractionation, reciprocal co-IP of p27 with NS, ubiquitylation and CDK2 activity assays with siRNA knockdown in hepatocellular carcinoma cells\",\n      \"pmids\": [\"27998760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for p27 ubiquitylation not identified\", \"Whether GTPase activity is required for this function untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GNL3 downstream of a transcriptional regulator by showing XBP1 binds the GNL3 promoter and that GNL3 is required for XBP1-driven proliferation and invasion.\",\n      \"evidence\": \"Dual-luciferase reporter assay, siRNA knockdown, and overexpression rescue in osteosarcoma cells\",\n      \"pmids\": [\"30936750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of GNL3 in the XBP1 axis not defined\", \"Single cell-context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked GNL3 to stem-like tumor properties through SIRT1, though without a direct regulatory mechanism.\",\n      \"evidence\": \"siRNA knockdown with SIRT1 Western blot, proliferation/invasion assays, and a subcutaneous xenograft model\",\n      \"pmids\": [\"35432540\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic link (ChIP/reporter) between GNL3 and SIRT1 transcription\", \"Single lab, single readout\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a genome-protective role in which GNL3 sequesters ORC2 to restrain origin firing and prevent RPA exhaustion and fork resection.\",\n      \"evidence\": \"DNA fiber resection assay, reciprocal GNL3-ORC2 co-IP, nucleolar fractionation, and origin-firing inhibition rescue\",\n      \"pmids\": [\"37965896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GNL3 nucleolar concentration is dynamically regulated during replication stress unclear\", \"Structural basis of GNL3-ORC2 binding unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that SUMOylation of GNL3 at K196 is the switch that recruits the BLM-DNA2 complex to drive homologous-recombination end resection.\",\n      \"evidence\": \"SUMOylation assays with K196R mutant, co-IP of GNL3 with BLM-DNA2, RPA/RAD51 loading assays, SENP3/USP36 manipulation, and breast cancer variant analysis (preprint)\",\n      \"pmids\": [\"41279596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer reviewed\", \"Apparent opposite effect on resection versus the ORC2 pathway not reconciled\", \"Functional impact of breast cancer variants in vivo untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established GNL3 as a dual transcriptional coregulator of the androgen receptor, simultaneously activating proliferation genes and repressing immune genes in castration-resistant prostate cancer.\",\n      \"evidence\": \"Proteomic profiling, reciprocal GNL3-AR co-IP, chromatin occupancy and reporter assays, knockdown with proliferation/metastasis/CD8+ T cell readouts\",\n      \"pmids\": [\"41772945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GTPase or nucleolar functions are required for AR coregulation unknown\", \"Direct corepressor recruitment mechanism at immune gene loci not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined GNL3 as a p53-regulatory node in which Lys-5 lactylation recruits ENO2 to displace MDM2, stabilizing p53 and driving chondrocyte senescence.\",\n      \"evidence\": \"Co-IP, GST pull-down, site-directed mutagenesis (E4A-ENO2, K5R-GNL3), lactylomics, and an in vivo mouse osteoarthritis model with ENO2 inhibitor\",\n      \"pmids\": [\"42192505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GNL3-MDM2 binding is coupled to MDM2 destabilization mechanistically unclear\", \"Relevance of the lactylation axis outside chondrocytes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GNL3's conserved nucleolar GTPase/ribosome-biogenesis activity mechanistically connects to its diverse roles in DNA replication, HR repair, p27/p53 regulation, and AR transcription.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model unifying the GTPase domain with the genome-integrity and transcriptional functions\", \"Whether nucleotide binding is required for the non-ribosomal functions untested\", \"Apparent opposing roles in limiting versus promoting resection unreconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DBP10\", \"ORC2\", \"BLM\", \"DNA2\", \"USP36\", \"SENP3\", \"AR\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}