{"gene":"GNL3L","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2009,"finding":"GNL3L binds TRF1 in the nucleoplasm, promotes TRF1 homodimerization and telomeric association, prevents PML body recruitment of telomere-bound TRF1, and stabilizes TRF1 protein by inhibiting its ubiquitylation and blocking its binding to FBX4 (an E3 ubiquitin ligase for TRF1). This TRF1-stabilizing activity mediates the mitotic increase of TRF1 and promotes the metaphase-to-anaphase transition.","method":"Co-immunoprecipitation, in vivo ubiquitylation assay, co-localization/live imaging, loss-of-function (siRNA) with mitotic phenotype readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitylation assay, imaging, functional rescue) in a single rigorous study","pmids":["19487455"],"is_preprint":false},{"year":2009,"finding":"GNL3L stabilizes TRF1 protein during mitosis through a nucleolar modulation mechanism, contrasting with nucleostemin which promotes TRF1 degradation; together they create dynamic control of TRF1 levels at the telomere and cell cycle.","method":"Review/commentary extending findings from Co-IP and functional studies","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 — review article synthesizing prior experimental data without new primary experiments","pmids":["19713769"],"is_preprint":false},{"year":2010,"finding":"GNL3L binds MDM2 in the nucleoplasm and stabilizes MDM2 protein by preventing its ubiquitylation, thereby suppressing p53 transcriptional targets (Bax, 14-3-3σ, p21). GNL3L depletion triggers G2/M arrest in a p53-dependent manner.","method":"Co-immunoprecipitation, in vivo ubiquitylation assay, siRNA knockdown, cell cycle analysis, reporter assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, ubiquitylation assay, and functional cell cycle phenotype","pmids":["21132010"],"is_preprint":false},{"year":2005,"finding":"GNL3L (and its fission yeast orthologue Grn1p) is required for processing of nucleolar pre-rRNA and nuclear export of ribosomal proteins. siRNA knockdown in HeLa cells confirmed the requirement of GNL3L for cell growth, and heterologous GNL3L expression rescued pre-rRNA processing and ribosomal protein export in Grn1-null yeast.","method":"siRNA knockdown in HeLa cells, genetic complementation in yeast (Δgrn1 rescue), Northern blot for rRNA processing, fluorescence microscopy for ribosomal protein export","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — functional rescue, siRNA knockdown, and rRNA processing assays across two organisms","pmids":["16251348"],"is_preprint":false},{"year":2014,"finding":"GNL3L depletion markedly impairs ribosome production without inducing appreciable DNA damage, demonstrating that GNL3L retained the ancestral invertebrate GNL3 role in ribosome biosynthesis, while its paralog nucleostemin acquired a genome-protective function.","method":"siRNA knockdown, ribosome production assay, DNA damage markers (γH2AX), rRNA synthesis measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — comparative loss-of-function with multiple functional readouts distinguishing GNL3L from nucleostemin","pmids":["24610951"],"is_preprint":false},{"year":2007,"finding":"GNL3L interacts with estrogen-related receptor gamma (ERRγ) via the intermediate domain of GNL3L and the AF2-domain of ERRγ, and inhibits ERR transcriptional activity by competing with steroid receptor coactivator (SRC) for ERRγ binding. This inhibition does not require nucleolar localization of GNL3L.","method":"Co-immunoprecipitation, domain mapping (deletion mutants), cell-based transcriptional reporter assay, SRC binding competition assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, functional reporter assay, and mechanistic competition assay","pmids":["17623774"],"is_preprint":false},{"year":2006,"finding":"GNL3L contains a novel lysine-rich nucleolar localization signal (NoLS, aa 1–50) that is necessary and sufficient to target heterologous proteins to the nucleolus via interaction with importin-β. GTP binding via the circularly permuted G-motifs is additionally required for efficient nucleolar retention, as G-domain mutations abrogate nucleolar retention even when NoLS is intact.","method":"Deletion mutagenesis, heterologous targeting assays, co-immunoprecipitation with importin-β, intracellular GTP depletion, site-directed mutagenesis of G-domain motifs","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of both NoLS and GTP-binding domains with direct functional localization readout","pmids":["17034816"],"is_preprint":false},{"year":2015,"finding":"GNL3L is a nucleo-cytoplasmic shuttling protein exported from the nucleus in a CRM1-dependent manner, via a nuclear export signal (NES) in the C-terminal domain (aa 501–582; key residues M567, L570, L572). Nuclear retention of GNL3L (NES-mutant) promotes S-phase progression by increasing Rb hyperphosphorylation (Ser780), E2F1, cyclin A2, and cyclin E1.","method":"Leptomycin B treatment, deletion/point mutagenesis, Co-IP with CRM1, cell cycle analysis, BrdU labeling, Western blot for cell cycle regulators","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis of NES, CRM1 interaction, and multiple cell cycle readouts","pmids":["26274615"],"is_preprint":false},{"year":2016,"finding":"GNL3L interacts with LDOC1, and LDOC1 expression destabilizes GNL3L protein and inhibits GNL3L-induced cell proliferation. GNL3L upregulates NF-κB transcriptional activity by modulating p65 expression, and the anti-apoptotic function of GNL3L requires p65.","method":"Co-immunoprecipitation, overexpression/knockdown, NF-κB reporter assay, TNF-α stimulation, p65 siRNA knockdown","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and reporter assays but single lab, moderate mechanistic depth","pmids":["27764577"],"is_preprint":false},{"year":2023,"finding":"GNL3L promotes autophagy in esophageal cancer cells via regulation of the AMPK signaling pathway; GNL3L overexpression activates AMPK and autophagic flux, while GNL3L silencing reduces these, and pharmacological or genetic inhibition of AMPK attenuates GNL3L-induced autophagy.","method":"siRNA knockdown, overexpression, Western blot for autophagy markers, AMPK agonist (AICAR) rescue, genetic AMPK inhibition","journal":"Medical oncology (Northwood, London, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain/loss-of-function with pharmacological and genetic rescue, but single lab","pmids":["38148364"],"is_preprint":false},{"year":2025,"finding":"GNL3L interacts with MDM2 in ESCC cells; GNL3L knockdown decreases MDM2 and increases p53 and p21, while MDM2 overexpression can reverse the effects of GNL3L silencing, establishing GNL3L as an upstream regulator of the MDM2-p53-p21 axis in ESCC progression.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, Western blot, in vivo xenograft","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis via rescue experiments plus Co-IP, single lab","pmids":["40856423"],"is_preprint":false},{"year":2026,"finding":"GNL3L associates with pre-60S ribosomal complexes and its GTPase activity (GTP binding and hydrolysis) is required for distinct steps of pre-rRNA processing, maintenance of 60S subunit levels, protein synthesis, and cellular proliferation. GTPase-inactive GNL3L accumulates on pre-60S particles together with other assembly factors at proximal binding sites.","method":"Cryo-EM/compositional analysis of pre-ribosomal particles, GTPase-inactive mutants, RNA crosslinking to map binding sites, ribosome profiling/synthesis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — structural/compositional analysis of pre-ribosomal particles combined with catalytic mutagenesis and functional ribosome assays","pmids":["41755636"],"is_preprint":false},{"year":2023,"finding":"GNL3L knockdown inhibits the ATM/p53 pathway (reducing ATM, p53, and p21 protein levels) in cigarette smoke/LPS-induced COPD models, alleviating inflammation and oxidative stress.","method":"siRNA knockdown in human bronchial epithelial cells, in vivo mouse COPD model, Western blot for ATM/p53/p21, ELISA for inflammatory cytokines","journal":"International journal of chronic obstructive pulmonary disease","confidence":"Low","confidence_rationale":"Tier 3 — single-lab KD with phenotypic readouts but limited mechanistic depth on how GNL3L engages ATM","pmids":["38022822"],"is_preprint":false},{"year":2025,"finding":"GNL3L promotes lung cancer cell proliferation, migration, and invasion by activating NF-κB and upregulating Slug, MMP2, and MMP9; overexpression of Slug plus NF-κB activation fully restores growth suppressed by GNL3L deficiency.","method":"siRNA knockdown and overexpression, NF-κB activation rescue, Slug/MMP2/MMP9 overexpression rescue, in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis via rescue experiments and in vivo validation, single lab","pmids":["40466800"],"is_preprint":false}],"current_model":"GNL3L is a nucleolar GTPase (HSR1/MMR1 family with circularly permuted G-motifs) that requires both a lysine-rich NoLS and GTP binding for nucleolar retention; it shuttles to the nucleoplasm in a CRM1-dependent manner and there performs multiple functions: it stabilizes TRF1 (by blocking FBX4-mediated ubiquitylation) to promote the metaphase-to-anaphase transition, stabilizes MDM2 (by preventing its ubiquitylation) to suppress p53 target gene expression, and inhibits ERRγ transcription by competing with SRC coactivators; in the nucleolus, its GTPase activity drives pre-60S rRNA processing and ribosome biogenesis; GNL3L also activates NF-κB signaling (modulating p65, Slug, MMP2, MMP9) and promotes autophagy via AMPK, and its activity is antagonized by the interacting partner LDOC1."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that GNL3L is required for pre-rRNA processing and ribosomal protein export answered the fundamental question of its ancestral cellular function — ribosome biogenesis — and showed conservation from fission yeast to human.","evidence":"siRNA knockdown in HeLa cells plus genetic rescue of Δgrn1 yeast with human GNL3L, Northern blot for rRNA, and ribosomal protein export assays","pmids":["16251348"],"confidence":"High","gaps":["Precise step in ribosome assembly where GNL3L acts was not resolved","Whether GTPase activity per se was required for rRNA processing was untested"]},{"year":2006,"claim":"Identification of a lysine-rich NoLS (aa 1–50) and the requirement of GTP binding for nucleolar retention defined the dual-signal mechanism governing GNL3L subnuclear targeting.","evidence":"Deletion/point mutagenesis, importin-β Co-IP, intracellular GTP depletion, heterologous targeting assays","pmids":["17034816"],"confidence":"High","gaps":["Whether importin-β interaction is direct or bridged by an adaptor was not distinguished","Mechanism of GTP-dependent retention (tethering to rDNA vs. pre-ribosomal particles) was unknown"]},{"year":2007,"claim":"Discovery that GNL3L inhibits ERRγ transcription by competing with SRC coactivators for ERRγ AF2-domain binding revealed a nucleoplasmic transcriptional regulatory function independent of nucleolar localization.","evidence":"Co-IP with domain mapping, SRC competition assay, transcriptional reporter in mammalian cells","pmids":["17623774"],"confidence":"High","gaps":["Physiological context triggering GNL3L–ERRγ interaction was not identified","Whether this extends to other nuclear receptors was untested"]},{"year":2009,"claim":"Demonstrating that GNL3L stabilizes TRF1 by blocking FBX4-mediated ubiquitylation and that this promotes the metaphase-to-anaphase transition established GNL3L as a cell-cycle-dependent regulator of telomere-binding protein homeostasis.","evidence":"Co-IP, in vivo ubiquitylation assay, live imaging, siRNA with mitotic phenotype readout in HeLa cells","pmids":["19487455"],"confidence":"High","gaps":["How GNL3L itself is regulated during mitosis was unclear","Whether TRF1 stabilization affects telomere length maintenance long-term was not assessed"]},{"year":2010,"claim":"Finding that GNL3L stabilizes MDM2 by preventing its ubiquitylation and thereby suppresses p53 target genes showed a second nucleoplasmic substrate-stabilizing mechanism, linking GNL3L to the p53 pathway.","evidence":"Co-IP, in vivo ubiquitylation assay, siRNA knockdown with cell cycle analysis and p53 reporter assay","pmids":["21132010"],"confidence":"High","gaps":["How GNL3L discriminates between TRF1- and MDM2-stabilization contexts was unknown","Direct structural basis for MDM2 ubiquitylation blockade was not resolved"]},{"year":2014,"claim":"Comparative loss-of-function analysis established that GNL3L retained the ancestral ribosome biogenesis function while its paralog nucleostemin diverged to genome protection, clarifying the functional split between the two HSR1/MMR1 family members.","evidence":"siRNA knockdown with ribosome production and DNA damage marker (γH2AX) assays in human cells","pmids":["24610951"],"confidence":"High","gaps":["Whether GNL3L has any secondary DNA damage role under specific stresses remained untested"]},{"year":2015,"claim":"Identification of a CRM1-dependent NES (aa 501–582) and demonstration that nuclear-retained GNL3L drives S-phase progression via Rb–E2F1 axis activation defined the export mechanism and revealed that nucleoplasmic GNL3L abundance controls cell cycle entry.","evidence":"Leptomycin B treatment, NES mutagenesis, CRM1 Co-IP, BrdU labeling, Western blot for Rb phosphorylation and cyclins","pmids":["26274615"],"confidence":"High","gaps":["Whether CRM1 export is regulated by post-translational modification was not tested","How nuclear GNL3L promotes Rb hyperphosphorylation mechanistically was not defined"]},{"year":2016,"claim":"Discovery that LDOC1 destabilizes GNL3L and that GNL3L activates NF-κB via p65 identified both a negative regulator and a pro-survival signaling output of GNL3L.","evidence":"Co-IP, overexpression/knockdown, NF-κB reporter assay, TNF-α stimulation, p65 siRNA epistasis","pmids":["27764577"],"confidence":"Medium","gaps":["Mechanism by which LDOC1 destabilizes GNL3L (proteasomal vs. other) was not determined","How GNL3L modulates p65 levels was unexplored"]},{"year":2023,"claim":"Linking GNL3L to AMPK-dependent autophagy in esophageal cancer cells expanded its functional repertoire beyond ribosome biogenesis and transcription factor stabilization.","evidence":"Gain/loss-of-function with autophagy markers, AMPK agonist rescue, genetic AMPK inhibition in ESCC cells","pmids":["38148364"],"confidence":"Medium","gaps":["Direct physical interaction with AMPK or upstream kinase not demonstrated","Relevance to non-cancer autophagy contexts untested"]},{"year":2025,"claim":"Epistasis experiments confirming GNL3L as an upstream regulator of the MDM2–p53–p21 axis in ESCC, and demonstration that NF-κB–Slug–MMP2/9 mediates GNL3L-driven invasion, consolidated its oncogenic signaling roles with in vivo validation.","evidence":"Co-IP, siRNA/overexpression rescue, in vivo xenografts in ESCC and lung cancer models","pmids":["40856423","40466800"],"confidence":"Medium","gaps":["Whether GNL3L's ribosome biogenesis and oncogenic signaling functions are separable was not tested","Structural basis for GNL3L–MDM2 interaction remains unknown"]},{"year":2026,"claim":"Structural and biochemical dissection of GNL3L on pre-60S particles showed that GTP binding and hydrolysis drive distinct pre-rRNA processing steps and that GTPase-inactive mutants accumulate on particles, providing the first mechanistic model for how GNL3L's enzymatic cycle promotes 60S biogenesis.","evidence":"Cryo-EM/compositional analysis of pre-ribosomal particles, GTPase-inactive mutants, RNA crosslinking, ribosome profiling","pmids":["41755636"],"confidence":"High","gaps":["Full atomic-resolution structure of GNL3L on the pre-60S particle not yet available","Identity of the GTPase-activating factor for GNL3L is unknown"]},{"year":null,"claim":"How GNL3L's nucleolar ribosome biogenesis function is coordinated with its nucleoplasmic roles in TRF1/MDM2 stabilization and NF-κB activation, and whether these functions are mutually exclusive or simultaneously active, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No separation-of-function mutant isolating ribosome biogenesis from signaling roles","Post-translational regulation of GNL3L partitioning between nucleolus and nucleoplasm is uncharacterized","No structural model of full-length GNL3L with any nucleoplasmic partner"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[3,6,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,6,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,2,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3,4,11]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,4,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]}],"complexes":["pre-60S ribosomal particle"],"partners":["TRF1","MDM2","ESRRG","FBX4","CRM1","LDOC1","KPNB1"],"other_free_text":[]},"mechanistic_narrative":"GNL3L is a nucleolar GTPase of the HSR1/MMR1 family that functions as a central regulator of ribosome biogenesis and cell cycle progression. Its GTPase activity, driven by circularly permuted G-motifs, is required for pre-60S rRNA processing, 60S subunit maintenance, and protein synthesis, while a lysine-rich nucleolar localization signal and GTP binding cooperate for nucleolar retention [PMID:16251348, PMID:41755636, PMID:17034816]. In the nucleoplasm, GNL3L stabilizes TRF1 by blocking FBX4-mediated ubiquitylation to promote the metaphase-to-anaphase transition, and stabilizes MDM2 by preventing its ubiquitylation to suppress p53 target gene expression and G2/M arrest [PMID:19487455, PMID:21132010]. GNL3L additionally inhibits ERRγ transcription by competing with SRC coactivators, activates NF-κB signaling through modulation of p65, and promotes autophagy via the AMPK pathway [PMID:17623774, PMID:27764577, PMID:38148364]."},"prefetch_data":{"uniprot":{"accession":"Q9NVN8","full_name":"Guanine nucleotide-binding protein-like 3-like protein","aliases":[],"length_aa":582,"mass_kda":65.6,"function":"Stabilizes TERF1 telomeric association by preventing TERF1 recruitment by PML. Stabilizes TERF1 protein by preventing its ubiquitination and hence proteasomal degradation. Does so by interfering with TERF1-binding to FBXO4 E3 ubiquitin-protein ligase. Required for cell proliferation. By stabilizing TRF1 protein during mitosis, promotes metaphase-to-anaphase transition. Stabilizes MDM2 protein by preventing its ubiquitination, and hence proteasomal degradation. By acting on MDM2, may affect TP53 activity. Required for normal processing of ribosomal pre-rRNA. Binds GTP","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9NVN8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GNL3L","classification":"Common Essential","n_dependent_lines":1108,"n_total_lines":1208,"dependency_fraction":0.9172185430463576},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GNL3L","total_profiled":1310},"omim":[{"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":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GNL3L"},"hgnc":{"alias_symbol":["FLJ10613","GNL3B"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVN8","domains":[{"cath_id":"3.40.50.300","chopping":"117-310_410-444","consensus_level":"high","plddt":81.5314,"start":117,"end":444},{"cath_id":"1.10.1580","chopping":"313-393","consensus_level":"medium","plddt":90.52,"start":313,"end":393},{"cath_id":"-","chopping":"461-489","consensus_level":"medium","plddt":45.7134,"start":461,"end":489}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVN8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVN8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVN8-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNL3L","jax_strain_url":"https://www.jax.org/strain/search?query=GNL3L"},"sequence":{"accession":"Q9NVN8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVN8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVN8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVN8"}},"corpus_meta":[{"pmid":"19487455","id":"PMC_19487455","title":"GNL3L stabilizes the TRF1 complex and promotes mitotic transition.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19487455","citation_count":46,"is_preprint":false},{"pmid":"16251348","id":"PMC_16251348","title":"The homologous putative GTPases Grn1p from fission yeast and the human GNL3L are required for growth and play a role in processing of nucleolar pre-rRNA.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16251348","citation_count":42,"is_preprint":false},{"pmid":"21132010","id":"PMC_21132010","title":"GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21132010","citation_count":36,"is_preprint":false},{"pmid":"24610951","id":"PMC_24610951","title":"Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24610951","citation_count":33,"is_preprint":false},{"pmid":"27764577","id":"PMC_27764577","title":"Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27764577","citation_count":28,"is_preprint":false},{"pmid":"17623774","id":"PMC_17623774","title":"GNL3L inhibits activity of estrogen-related receptor gamma by competing for coactivator binding.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17623774","citation_count":27,"is_preprint":false},{"pmid":"32422901","id":"PMC_32422901","title":"Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32422901","citation_count":25,"is_preprint":false},{"pmid":"17034816","id":"PMC_17034816","title":"A novel lysine-rich domain and GTP binding motifs regulate the nucleolar retention of human guanine nucleotide binding protein, GNL3L.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17034816","citation_count":21,"is_preprint":false},{"pmid":"26274615","id":"PMC_26274615","title":"GNL3L Is a Nucleo-Cytoplasmic Shuttling Protein: Role in Cell Cycle Regulation.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26274615","citation_count":19,"is_preprint":false},{"pmid":"19713769","id":"PMC_19713769","title":"Nucleolar modulation of TRF1: a dynamic way to regulate telomere and cell cycle by nucleostemin and GNL3L.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19713769","citation_count":14,"is_preprint":false},{"pmid":"38022822","id":"PMC_38022822","title":"Knockdown of GNL3L Alleviates the Progression of COPD Through Inhibiting the ATM/p53 Pathway.","date":"2023","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/38022822","citation_count":7,"is_preprint":false},{"pmid":"37635478","id":"PMC_37635478","title":"Calycosin inhibits gemcitabine-resistant lung cancer cells proliferation through modulation of the LDOC1/GNL3L/NFκB.","date":"2023","source":"The Chinese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37635478","citation_count":6,"is_preprint":false},{"pmid":"38148364","id":"PMC_38148364","title":"GNL3L promotes autophagy via regulating AMPK signaling in esophageal cancer cells.","date":"2023","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38148364","citation_count":5,"is_preprint":false},{"pmid":"40856423","id":"PMC_40856423","title":"The GNL3L-MDM2 Interaction Drives Esophageal Squamous Cell Carcinoma Progression.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40856423","citation_count":0,"is_preprint":false},{"pmid":"41755636","id":"PMC_41755636","title":"Distinct steps of nuclear maturation of human pre-60S complexes require the activity of GTPases including GNL3L.","date":"2026","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41755636","citation_count":0,"is_preprint":false},{"pmid":"38738247","id":"PMC_38738247","title":"Revealing the oncogenic role of elevated GNL3L expression in esophageal squamous cell carcinoma: insights into the STAT3 pathway.","date":"2024","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/38738247","citation_count":0,"is_preprint":false},{"pmid":"40466800","id":"PMC_40466800","title":"Role of GNL3L in lung cancer: Mediating proliferation and progression through NF-κB pathway activation and upregulation of Slug, MMP2, and MMP9.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40466800","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9723,"output_tokens":3457,"usd":0.040512},"stage2":{"model":"claude-opus-4-6","input_tokens":6906,"output_tokens":3003,"usd":0.164408},"total_usd":0.20492,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"GNL3L binds TRF1 in the nucleoplasm, promotes TRF1 homodimerization and telomeric association, prevents PML body recruitment of telomere-bound TRF1, and stabilizes TRF1 protein by inhibiting its ubiquitylation and blocking its binding to FBX4 (an E3 ubiquitin ligase for TRF1). This TRF1-stabilizing activity mediates the mitotic increase of TRF1 and promotes the metaphase-to-anaphase transition.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitylation assay, co-localization/live imaging, loss-of-function (siRNA) with mitotic phenotype readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitylation assay, imaging, functional rescue) in a single rigorous study\",\n      \"pmids\": [\"19487455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GNL3L stabilizes TRF1 protein during mitosis through a nucleolar modulation mechanism, contrasting with nucleostemin which promotes TRF1 degradation; together they create dynamic control of TRF1 levels at the telomere and cell cycle.\",\n      \"method\": \"Review/commentary extending findings from Co-IP and functional studies\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review article synthesizing prior experimental data without new primary experiments\",\n      \"pmids\": [\"19713769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GNL3L binds MDM2 in the nucleoplasm and stabilizes MDM2 protein by preventing its ubiquitylation, thereby suppressing p53 transcriptional targets (Bax, 14-3-3σ, p21). GNL3L depletion triggers G2/M arrest in a p53-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitylation assay, siRNA knockdown, cell cycle analysis, reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, ubiquitylation assay, and functional cell cycle phenotype\",\n      \"pmids\": [\"21132010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GNL3L (and its fission yeast orthologue Grn1p) is required for processing of nucleolar pre-rRNA and nuclear export of ribosomal proteins. siRNA knockdown in HeLa cells confirmed the requirement of GNL3L for cell growth, and heterologous GNL3L expression rescued pre-rRNA processing and ribosomal protein export in Grn1-null yeast.\",\n      \"method\": \"siRNA knockdown in HeLa cells, genetic complementation in yeast (Δgrn1 rescue), Northern blot for rRNA processing, fluorescence microscopy for ribosomal protein export\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue, siRNA knockdown, and rRNA processing assays across two organisms\",\n      \"pmids\": [\"16251348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GNL3L depletion markedly impairs ribosome production without inducing appreciable DNA damage, demonstrating that GNL3L retained the ancestral invertebrate GNL3 role in ribosome biosynthesis, while its paralog nucleostemin acquired a genome-protective function.\",\n      \"method\": \"siRNA knockdown, ribosome production assay, DNA damage markers (γH2AX), rRNA synthesis measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comparative loss-of-function with multiple functional readouts distinguishing GNL3L from nucleostemin\",\n      \"pmids\": [\"24610951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GNL3L interacts with estrogen-related receptor gamma (ERRγ) via the intermediate domain of GNL3L and the AF2-domain of ERRγ, and inhibits ERR transcriptional activity by competing with steroid receptor coactivator (SRC) for ERRγ binding. This inhibition does not require nucleolar localization of GNL3L.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (deletion mutants), cell-based transcriptional reporter assay, SRC binding competition assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, functional reporter assay, and mechanistic competition assay\",\n      \"pmids\": [\"17623774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GNL3L contains a novel lysine-rich nucleolar localization signal (NoLS, aa 1–50) that is necessary and sufficient to target heterologous proteins to the nucleolus via interaction with importin-β. GTP binding via the circularly permuted G-motifs is additionally required for efficient nucleolar retention, as G-domain mutations abrogate nucleolar retention even when NoLS is intact.\",\n      \"method\": \"Deletion mutagenesis, heterologous targeting assays, co-immunoprecipitation with importin-β, intracellular GTP depletion, site-directed mutagenesis of G-domain motifs\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of both NoLS and GTP-binding domains with direct functional localization readout\",\n      \"pmids\": [\"17034816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GNL3L is a nucleo-cytoplasmic shuttling protein exported from the nucleus in a CRM1-dependent manner, via a nuclear export signal (NES) in the C-terminal domain (aa 501–582; key residues M567, L570, L572). Nuclear retention of GNL3L (NES-mutant) promotes S-phase progression by increasing Rb hyperphosphorylation (Ser780), E2F1, cyclin A2, and cyclin E1.\",\n      \"method\": \"Leptomycin B treatment, deletion/point mutagenesis, Co-IP with CRM1, cell cycle analysis, BrdU labeling, Western blot for cell cycle regulators\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of NES, CRM1 interaction, and multiple cell cycle readouts\",\n      \"pmids\": [\"26274615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GNL3L interacts with LDOC1, and LDOC1 expression destabilizes GNL3L protein and inhibits GNL3L-induced cell proliferation. GNL3L upregulates NF-κB transcriptional activity by modulating p65 expression, and the anti-apoptotic function of GNL3L requires p65.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, NF-κB reporter assay, TNF-α stimulation, p65 siRNA knockdown\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and reporter assays but single lab, moderate mechanistic depth\",\n      \"pmids\": [\"27764577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNL3L promotes autophagy in esophageal cancer cells via regulation of the AMPK signaling pathway; GNL3L overexpression activates AMPK and autophagic flux, while GNL3L silencing reduces these, and pharmacological or genetic inhibition of AMPK attenuates GNL3L-induced autophagy.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot for autophagy markers, AMPK agonist (AICAR) rescue, genetic AMPK inhibition\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain/loss-of-function with pharmacological and genetic rescue, but single lab\",\n      \"pmids\": [\"38148364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GNL3L interacts with MDM2 in ESCC cells; GNL3L knockdown decreases MDM2 and increases p53 and p21, while MDM2 overexpression can reverse the effects of GNL3L silencing, establishing GNL3L as an upstream regulator of the MDM2-p53-p21 axis in ESCC progression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, Western blot, in vivo xenograft\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis via rescue experiments plus Co-IP, single lab\",\n      \"pmids\": [\"40856423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GNL3L associates with pre-60S ribosomal complexes and its GTPase activity (GTP binding and hydrolysis) is required for distinct steps of pre-rRNA processing, maintenance of 60S subunit levels, protein synthesis, and cellular proliferation. GTPase-inactive GNL3L accumulates on pre-60S particles together with other assembly factors at proximal binding sites.\",\n      \"method\": \"Cryo-EM/compositional analysis of pre-ribosomal particles, GTPase-inactive mutants, RNA crosslinking to map binding sites, ribosome profiling/synthesis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural/compositional analysis of pre-ribosomal particles combined with catalytic mutagenesis and functional ribosome assays\",\n      \"pmids\": [\"41755636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNL3L knockdown inhibits the ATM/p53 pathway (reducing ATM, p53, and p21 protein levels) in cigarette smoke/LPS-induced COPD models, alleviating inflammation and oxidative stress.\",\n      \"method\": \"siRNA knockdown in human bronchial epithelial cells, in vivo mouse COPD model, Western blot for ATM/p53/p21, ELISA for inflammatory cytokines\",\n      \"journal\": \"International journal of chronic obstructive pulmonary disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single-lab KD with phenotypic readouts but limited mechanistic depth on how GNL3L engages ATM\",\n      \"pmids\": [\"38022822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GNL3L promotes lung cancer cell proliferation, migration, and invasion by activating NF-κB and upregulating Slug, MMP2, and MMP9; overexpression of Slug plus NF-κB activation fully restores growth suppressed by GNL3L deficiency.\",\n      \"method\": \"siRNA knockdown and overexpression, NF-κB activation rescue, Slug/MMP2/MMP9 overexpression rescue, in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis via rescue experiments and in vivo validation, single lab\",\n      \"pmids\": [\"40466800\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNL3L is a nucleolar GTPase (HSR1/MMR1 family with circularly permuted G-motifs) that requires both a lysine-rich NoLS and GTP binding for nucleolar retention; it shuttles to the nucleoplasm in a CRM1-dependent manner and there performs multiple functions: it stabilizes TRF1 (by blocking FBX4-mediated ubiquitylation) to promote the metaphase-to-anaphase transition, stabilizes MDM2 (by preventing its ubiquitylation) to suppress p53 target gene expression, and inhibits ERRγ transcription by competing with SRC coactivators; in the nucleolus, its GTPase activity drives pre-60S rRNA processing and ribosome biogenesis; GNL3L also activates NF-κB signaling (modulating p65, Slug, MMP2, MMP9) and promotes autophagy via AMPK, and its activity is antagonized by the interacting partner LDOC1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GNL3L is a nucleolar GTPase of the HSR1/MMR1 family that functions as a central regulator of ribosome biogenesis and cell cycle progression. Its GTPase activity, driven by circularly permuted G-motifs, is required for pre-60S rRNA processing, 60S subunit maintenance, and protein synthesis, while a lysine-rich nucleolar localization signal and GTP binding cooperate for nucleolar retention [PMID:16251348, PMID:41755636, PMID:17034816]. In the nucleoplasm, GNL3L stabilizes TRF1 by blocking FBX4-mediated ubiquitylation to promote the metaphase-to-anaphase transition, and stabilizes MDM2 by preventing its ubiquitylation to suppress p53 target gene expression and G2/M arrest [PMID:19487455, PMID:21132010]. GNL3L additionally inhibits ERRγ transcription by competing with SRC coactivators, activates NF-κB signaling through modulation of p65, and promotes autophagy via the AMPK pathway [PMID:17623774, PMID:27764577, PMID:38148364].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that GNL3L is required for pre-rRNA processing and ribosomal protein export answered the fundamental question of its ancestral cellular function — ribosome biogenesis — and showed conservation from fission yeast to human.\",\n      \"evidence\": \"siRNA knockdown in HeLa cells plus genetic rescue of Δgrn1 yeast with human GNL3L, Northern blot for rRNA, and ribosomal protein export assays\",\n      \"pmids\": [\"16251348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise step in ribosome assembly where GNL3L acts was not resolved\", \"Whether GTPase activity per se was required for rRNA processing was untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of a lysine-rich NoLS (aa 1–50) and the requirement of GTP binding for nucleolar retention defined the dual-signal mechanism governing GNL3L subnuclear targeting.\",\n      \"evidence\": \"Deletion/point mutagenesis, importin-β Co-IP, intracellular GTP depletion, heterologous targeting assays\",\n      \"pmids\": [\"17034816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether importin-β interaction is direct or bridged by an adaptor was not distinguished\", \"Mechanism of GTP-dependent retention (tethering to rDNA vs. pre-ribosomal particles) was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that GNL3L inhibits ERRγ transcription by competing with SRC coactivators for ERRγ AF2-domain binding revealed a nucleoplasmic transcriptional regulatory function independent of nucleolar localization.\",\n      \"evidence\": \"Co-IP with domain mapping, SRC competition assay, transcriptional reporter in mammalian cells\",\n      \"pmids\": [\"17623774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context triggering GNL3L–ERRγ interaction was not identified\", \"Whether this extends to other nuclear receptors was untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that GNL3L stabilizes TRF1 by blocking FBX4-mediated ubiquitylation and that this promotes the metaphase-to-anaphase transition established GNL3L as a cell-cycle-dependent regulator of telomere-binding protein homeostasis.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitylation assay, live imaging, siRNA with mitotic phenotype readout in HeLa cells\",\n      \"pmids\": [\"19487455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GNL3L itself is regulated during mitosis was unclear\", \"Whether TRF1 stabilization affects telomere length maintenance long-term was not assessed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Finding that GNL3L stabilizes MDM2 by preventing its ubiquitylation and thereby suppresses p53 target genes showed a second nucleoplasmic substrate-stabilizing mechanism, linking GNL3L to the p53 pathway.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitylation assay, siRNA knockdown with cell cycle analysis and p53 reporter assay\",\n      \"pmids\": [\"21132010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GNL3L discriminates between TRF1- and MDM2-stabilization contexts was unknown\", \"Direct structural basis for MDM2 ubiquitylation blockade was not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Comparative loss-of-function analysis established that GNL3L retained the ancestral ribosome biogenesis function while its paralog nucleostemin diverged to genome protection, clarifying the functional split between the two HSR1/MMR1 family members.\",\n      \"evidence\": \"siRNA knockdown with ribosome production and DNA damage marker (γH2AX) assays in human cells\",\n      \"pmids\": [\"24610951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GNL3L has any secondary DNA damage role under specific stresses remained untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of a CRM1-dependent NES (aa 501–582) and demonstration that nuclear-retained GNL3L drives S-phase progression via Rb–E2F1 axis activation defined the export mechanism and revealed that nucleoplasmic GNL3L abundance controls cell cycle entry.\",\n      \"evidence\": \"Leptomycin B treatment, NES mutagenesis, CRM1 Co-IP, BrdU labeling, Western blot for Rb phosphorylation and cyclins\",\n      \"pmids\": [\"26274615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRM1 export is regulated by post-translational modification was not tested\", \"How nuclear GNL3L promotes Rb hyperphosphorylation mechanistically was not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that LDOC1 destabilizes GNL3L and that GNL3L activates NF-κB via p65 identified both a negative regulator and a pro-survival signaling output of GNL3L.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, NF-κB reporter assay, TNF-α stimulation, p65 siRNA epistasis\",\n      \"pmids\": [\"27764577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LDOC1 destabilizes GNL3L (proteasomal vs. other) was not determined\", \"How GNL3L modulates p65 levels was unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking GNL3L to AMPK-dependent autophagy in esophageal cancer cells expanded its functional repertoire beyond ribosome biogenesis and transcription factor stabilization.\",\n      \"evidence\": \"Gain/loss-of-function with autophagy markers, AMPK agonist rescue, genetic AMPK inhibition in ESCC cells\",\n      \"pmids\": [\"38148364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with AMPK or upstream kinase not demonstrated\", \"Relevance to non-cancer autophagy contexts untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Epistasis experiments confirming GNL3L as an upstream regulator of the MDM2–p53–p21 axis in ESCC, and demonstration that NF-κB–Slug–MMP2/9 mediates GNL3L-driven invasion, consolidated its oncogenic signaling roles with in vivo validation.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression rescue, in vivo xenografts in ESCC and lung cancer models\",\n      \"pmids\": [\"40856423\", \"40466800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GNL3L's ribosome biogenesis and oncogenic signaling functions are separable was not tested\", \"Structural basis for GNL3L–MDM2 interaction remains unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Structural and biochemical dissection of GNL3L on pre-60S particles showed that GTP binding and hydrolysis drive distinct pre-rRNA processing steps and that GTPase-inactive mutants accumulate on particles, providing the first mechanistic model for how GNL3L's enzymatic cycle promotes 60S biogenesis.\",\n      \"evidence\": \"Cryo-EM/compositional analysis of pre-ribosomal particles, GTPase-inactive mutants, RNA crosslinking, ribosome profiling\",\n      \"pmids\": [\"41755636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of GNL3L on the pre-60S particle not yet available\", \"Identity of the GTPase-activating factor for GNL3L is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GNL3L's nucleolar ribosome biogenesis function is coordinated with its nucleoplasmic roles in TRF1/MDM2 stabilization and NF-κB activation, and whether these functions are mutually exclusive or simultaneously active, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No separation-of-function mutant isolating ribosome biogenesis from signaling roles\", \"Post-translational regulation of GNL3L partitioning between nucleolus and nucleoplasm is uncharacterized\", \"No structural model of full-length GNL3L with any nucleoplasmic partner\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"pre-60S ribosomal particle\"\n    ],\n    \"partners\": [\n      \"TRF1\",\n      \"MDM2\",\n      \"ESRRG\",\n      \"FBX4\",\n      \"CRM1\",\n      \"LDOC1\",\n      \"KPNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}