{"gene":"NFRKB","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2015,"finding":"NFRKB (INO80G) inhibits the deubiquitylase UCH37/UCH-L5 by blocking its ubiquitin-binding site and disrupting the enzyme active site, as determined by crystal structures of the UCH37–NFRKB complex and biochemical characterization.","method":"Crystal structure determination and biochemical characterization of UCH37 in complex with NFRKB; active-site analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure solved with biochemical validation, replicated in two independent studies (PMID:25702870 and PMID:25702872)","pmids":["25702872","25702870"],"is_preprint":false},{"year":2015,"finding":"The DEUBAD domain of NFRKB (INO80G) inhibits UCH-L5 by exploiting UCH-L5 conformational plasticity to promote a radically different conformation from that induced by activator RPN13, and employs molecular mimicry to block ubiquitin docking on UCH-L5.","method":"Crystal structure determination of UCH-L5–INO80G DEUBAD domain complex; mutagenesis and biochemical activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mechanistic mutagenesis, independently replicated in companion paper (PMID:25702872)","pmids":["25702870"],"is_preprint":false},{"year":2014,"finding":"NFRKB is protected from proteasomal degradation by the deubiquitylase UCHL5, and this protection is required for UCHL5 to regulate DNA double-strand break resection and repair by homologous recombination.","method":"DUB siRNA screen, epistasis experiments, co-immunoprecipitation, DNA damage repair assays (DSB resection, HR reporter)","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional epistasis with clean KD and defined cellular phenotype (HR repair), single lab","pmids":["25194926"],"is_preprint":false},{"year":2012,"finding":"NFRKB contains a novel winged-helix-like domain (residues 370–495) that is mostly helical and does not bind DNA, suggesting it is involved in protein–protein interactions rather than direct DNA binding.","method":"High-throughput X-ray crystallography (JCSG pipeline); DNA-binding assay (negative result for DNA binding)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure solved in single study; DNA-binding negative result experimentally confirmed","pmids":["22984442"],"is_preprint":false},{"year":2012,"finding":"NFRKB is a component of the metazoan INO80 chromatin remodeling complex and undergoes post-translational modification by sumoylation; during minimal change nephrotic syndrome (MCNS) relapse it localizes predominantly to the nuclear compartment, whereas in remission it is restricted to the cytoplasm, and nuclear NFRKB induces AP1 signaling by upregulating c-jun and promotes genomic hypomethylation.","method":"Immunofluorescence localization, western blotting, SUMO modification assay, reporter/signaling assay, bisulfite sequencing for methylation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple assays but all correlative; mechanistic pathway placement (AP1/c-jun) not validated by rescue or mutagenesis","pmids":["22291976"],"is_preprint":false},{"year":2020,"finding":"lncRNA DRAIC binds UCHL5 and attenuates the interaction between UCHL5 and NFRKB, thereby promoting ubiquitin-mediated degradation of NFRKB protein and inhibiting gastric cancer cell proliferation and metastasis; overexpression of NFRKB rescues the DRAIC-induced inhibition.","method":"RNA-IP, Co-IP, ubiquitination-IP, CHX/MG132 treatment, CCK-8 proliferation and transwell invasion assays, rescue experiment with NFRKB overexpression","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-IP, Co-IP, ubiquitination assay, rescue) in single lab","pmids":["32351584"],"is_preprint":false},{"year":2021,"finding":"NFRKB is a telomere-associated protein in human ALT (alternative lengthening of telomeres) cells; loss of NFRKB induces telomere dysfunction and reduces PML bodies in U2OS cells, and NFRKB accumulates in the nucleus of liver cancer cells.","method":"Immunostaining, fluorescence in situ hybridization (FISH), siRNA loss-of-function, western blot, immunohistochemistry","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by immunostaining/FISH with functional consequence shown by KD phenotype; single lab","pmids":["34591601"],"is_preprint":false},{"year":2012,"finding":"Computational sequence analysis established that the DEUBAD domain is shared among NFRKB (INO80G), ADRM1 (RPN13), and ASXL1, indicating common ancestry of UCH37/UCH-L5 regulators across the INO80, proteasome, and PR-DUB complexes.","method":"Comparative sequence analysis / bioinformatics domain identification","journal":"Bioinformatics (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational prediction only; no direct biochemical experiment on NFRKB in this paper","pmids":["22645167"],"is_preprint":false}],"current_model":"NFRKB (INO80G) is a metazoan-specific subunit of the INO80 chromatin remodeling complex that recruits and potently inhibits the deubiquitylase UCH37/UCH-L5 via its DEUBAD domain—blocking ubiquitin docking and disrupting the UCH37 active site through allosteric conformational changes—while itself being stabilized by UCHL5-mediated deubiquitylation; this NFRKB–UCHL5 axis is required for efficient homologous recombination-based DNA double-strand break repair, and NFRKB additionally associates with telomeres in ALT cells to protect them from DNA damage."},"narrative":{"mechanistic_narrative":"NFRKB (INO80G) is a metazoan-specific subunit of the INO80 chromatin remodeling complex that functions principally as a regulator of the deubiquitylase UCH37/UCH-L5 [PMID:25702872, PMID:25702870, PMID:25194926]. Through its DEUBAD domain, NFRKB potently inhibits UCH-L5 by exploiting the enzyme's conformational plasticity to drive it into a conformation distinct from that imposed by the activator RPN13, and by molecular mimicry that blocks ubiquitin docking and disrupts the active site [PMID:25702872, PMID:25702870]. NFRKB also contains a winged-helix-like domain (residues 370–495) that does not bind DNA and instead mediates protein–protein interactions [PMID:22984442]. The NFRKB–UCHL5 relationship is reciprocal: UCHL5 deubiquitylates and stabilizes NFRKB against proteasomal degradation, and this stabilization is required for DNA double-strand break resection and homologous recombination repair [PMID:25194926]. This axis is modulated by the lncRNA DRAIC, which binds UCHL5, weakens its interaction with NFRKB, and thereby promotes NFRKB degradation to restrain gastric cancer cell proliferation and invasion [PMID:32351584]. NFRKB additionally associates with telomeres in alternative-lengthening-of-telomeres (ALT) cells, where its loss induces telomere dysfunction and reduces PML bodies [PMID:34591601].","teleology":[{"year":2012,"claim":"Defining NFRKB's structural architecture clarified whether it acts directly on DNA or through protein contacts, establishing that its winged-helix-like region serves protein-interaction rather than DNA-binding roles.","evidence":"High-throughput X-ray crystallography of residues 370–495 with a negative DNA-binding assay","pmids":["22984442"],"confidence":"Medium","gaps":["Function of regions outside 370–495 unresolved","Specific interaction partners of the winged-helix domain not identified"]},{"year":2012,"claim":"Bioinformatic identification of a shared DEUBAD domain across NFRKB, ADRM1, and ASXL1 placed NFRKB within a family of UCH37/UCH-L5 regulators, predicting a regulatory link later confirmed structurally.","evidence":"Comparative sequence analysis identifying the DEUBAD domain","pmids":["22645167"],"confidence":"Low","gaps":["Computational prediction only, no biochemistry on NFRKB","Did not establish direction of regulation (activation vs inhibition)"]},{"year":2014,"claim":"Functional epistasis revealed that UCHL5 stabilizes NFRKB and that this stabilization is required for homologous recombination, linking the NFRKB–UCHL5 pair to DNA double-strand break repair.","evidence":"DUB siRNA screen, co-IP, and HR reporter/DSB resection assays in human cells","pmids":["25194926"],"confidence":"Medium","gaps":["Single lab","Molecular role of NFRKB at break sites not defined","Whether INO80 complex integrity is required not tested"]},{"year":2015,"claim":"Crystal structures resolved how NFRKB inhibits UCH37/UCH-L5, showing it blocks the ubiquitin-binding site and disrupts the active site—the structural basis for its function as a DEUBAD-domain inhibitor.","evidence":"Crystal structures of the UCH37–NFRKB/INO80G DEUBAD complex with mutagenesis and activity assays, replicated across two studies","pmids":["25702872","25702870"],"confidence":"High","gaps":["Cellular substrates whose deubiquitylation is blocked not enumerated","How inhibition is relieved in vivo not addressed"]},{"year":2020,"claim":"Identifying lncRNA DRAIC as a competitor of the UCHL5–NFRKB interaction showed how NFRKB levels are tuned, connecting NFRKB stability to cancer cell proliferation and metastasis.","evidence":"RNA-IP, co-IP, ubiquitination assays, CHX/MG132 chase, and NFRKB-overexpression rescue in gastric cancer cells","pmids":["32351584"],"confidence":"Medium","gaps":["Single lab","Direct binding interfaces of DRAIC not mapped","Generalizability beyond gastric cancer unknown"]},{"year":2021,"claim":"Demonstrating telomere association in ALT cells extended NFRKB's genome-maintenance role beyond DSB repair to telomere protection.","evidence":"Immunostaining/FISH co-localization and siRNA loss-of-function showing telomere dysfunction and reduced PML bodies in U2OS cells","pmids":["34591601"],"confidence":"Medium","gaps":["Single lab","Mechanism of telomere recruitment unknown","Dependence on UCHL5 or INO80 complex not tested"]},{"year":null,"claim":"How NFRKB integrates INO80 chromatin remodeling, UCH-L5 inhibition, and genome maintenance into a unified pathway, and what substrates its inhibition of UCH-L5 protects, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined catalytic substrate set for the NFRKB-inhibited UCH-L5","Mechanistic link between INO80 remodeling and DSB/telomere roles unestablished","Recruitment determinants to chromatin and telomeres unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]}],"complexes":["INO80 chromatin remodeling complex"],"partners":["UCHL5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P4R8","full_name":"Nuclear factor related to kappa-B-binding protein","aliases":["DNA-binding protein R kappa-B","INO80 complex subunit G"],"length_aa":1299,"mass_kda":139.0,"function":"Binds to the DNA consensus sequence 5'-GGGGAATCTCC-3' Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Modulates the deubiquitinase activity of UCHL5 in the INO80 complex","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6P4R8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFRKB","classification":"Not Classified","n_dependent_lines":583,"n_total_lines":1208,"dependency_fraction":0.4826158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"INO80","stoichiometry":10.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"YY1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NFRKB","total_profiled":1310},"omim":[{"mim_id":"164013","title":"NUCLEAR FACTOR RELATED TO KAPPA-B BINDING PROTEIN; NFRKB","url":"https://www.omim.org/entry/164013"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NFRKB"},"hgnc":{"alias_symbol":["DKFZp547B2013","INO80G"],"prev_symbol":[]},"alphafold":{"accession":"Q6P4R8","domains":[{"cath_id":"-","chopping":"27-163","consensus_level":"medium","plddt":89.695,"start":27,"end":163},{"cath_id":"1.10.10.2430","chopping":"380-488","consensus_level":"high","plddt":80.5912,"start":380,"end":488},{"cath_id":"-","chopping":"516-675","consensus_level":"high","plddt":86.1453,"start":516,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4R8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4R8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4R8-F1-predicted_aligned_error_v6.png","plddt_mean":54.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFRKB","jax_strain_url":"https://www.jax.org/strain/search?query=NFRKB"},"sequence":{"accession":"Q6P4R8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P4R8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P4R8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4R8"}},"corpus_meta":[{"pmid":"25194926","id":"PMC_25194926","title":"Systematic 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active-site analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure solved with biochemical validation, replicated in two independent studies (PMID:25702870 and PMID:25702872)\",\n      \"pmids\": [\"25702872\", \"25702870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The DEUBAD domain of NFRKB (INO80G) inhibits UCH-L5 by exploiting UCH-L5 conformational plasticity to promote a radically different conformation from that induced by activator RPN13, and employs molecular mimicry to block ubiquitin docking on UCH-L5.\",\n      \"method\": \"Crystal structure determination of UCH-L5–INO80G DEUBAD domain complex; mutagenesis and biochemical activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mechanistic mutagenesis, independently replicated in companion paper (PMID:25702872)\",\n      \"pmids\": [\"25702870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NFRKB is protected from proteasomal degradation by the deubiquitylase UCHL5, and this protection is required for UCHL5 to regulate DNA double-strand break resection and repair by homologous recombination.\",\n      \"method\": \"DUB siRNA screen, epistasis experiments, co-immunoprecipitation, DNA damage repair assays (DSB resection, HR reporter)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional epistasis with clean KD and defined cellular phenotype (HR repair), single lab\",\n      \"pmids\": [\"25194926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NFRKB contains a novel winged-helix-like domain (residues 370–495) that is mostly helical and does not bind DNA, suggesting it is involved in protein–protein interactions rather than direct DNA binding.\",\n      \"method\": \"High-throughput X-ray crystallography (JCSG pipeline); DNA-binding assay (negative result for DNA binding)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure solved in single study; DNA-binding negative result experimentally confirmed\",\n      \"pmids\": [\"22984442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NFRKB is a component of the metazoan INO80 chromatin remodeling complex and undergoes post-translational modification by sumoylation; during minimal change nephrotic syndrome (MCNS) relapse it localizes predominantly to the nuclear compartment, whereas in remission it is restricted to the cytoplasm, and nuclear NFRKB induces AP1 signaling by upregulating c-jun and promotes genomic hypomethylation.\",\n      \"method\": \"Immunofluorescence localization, western blotting, SUMO modification assay, reporter/signaling assay, bisulfite sequencing for methylation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple assays but all correlative; mechanistic pathway placement (AP1/c-jun) not validated by rescue or mutagenesis\",\n      \"pmids\": [\"22291976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA DRAIC binds UCHL5 and attenuates the interaction between UCHL5 and NFRKB, thereby promoting ubiquitin-mediated degradation of NFRKB protein and inhibiting gastric cancer cell proliferation and metastasis; overexpression of NFRKB rescues the DRAIC-induced inhibition.\",\n      \"method\": \"RNA-IP, Co-IP, ubiquitination-IP, CHX/MG132 treatment, CCK-8 proliferation and transwell invasion assays, rescue experiment with NFRKB overexpression\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-IP, Co-IP, ubiquitination assay, rescue) in single lab\",\n      \"pmids\": [\"32351584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NFRKB is a telomere-associated protein in human ALT (alternative lengthening of telomeres) cells; loss of NFRKB induces telomere dysfunction and reduces PML bodies in U2OS cells, and NFRKB accumulates in the nucleus of liver cancer cells.\",\n      \"method\": \"Immunostaining, fluorescence in situ hybridization (FISH), siRNA loss-of-function, western blot, immunohistochemistry\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by immunostaining/FISH with functional consequence shown by KD phenotype; single lab\",\n      \"pmids\": [\"34591601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Computational sequence analysis established that the DEUBAD domain is shared among NFRKB (INO80G), ADRM1 (RPN13), and ASXL1, indicating common ancestry of UCH37/UCH-L5 regulators across the INO80, proteasome, and PR-DUB complexes.\",\n      \"method\": \"Comparative sequence analysis / bioinformatics domain identification\",\n      \"journal\": \"Bioinformatics (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational prediction only; no direct biochemical experiment on NFRKB in this paper\",\n      \"pmids\": [\"22645167\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFRKB (INO80G) is a metazoan-specific subunit of the INO80 chromatin remodeling complex that recruits and potently inhibits the deubiquitylase UCH37/UCH-L5 via its DEUBAD domain—blocking ubiquitin docking and disrupting the UCH37 active site through allosteric conformational changes—while itself being stabilized by UCHL5-mediated deubiquitylation; this NFRKB–UCHL5 axis is required for efficient homologous recombination-based DNA double-strand break repair, and NFRKB additionally associates with telomeres in ALT cells to protect them from DNA damage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFRKB (INO80G) is a metazoan-specific subunit of the INO80 chromatin remodeling complex that functions principally as a regulator of the deubiquitylase UCH37/UCH-L5 [#0, #2]. Through its DEUBAD domain, NFRKB potently inhibits UCH-L5 by exploiting the enzyme's conformational plasticity to drive it into a conformation distinct from that imposed by the activator RPN13, and by molecular mimicry that blocks ubiquitin docking and disrupts the active site [#0, #1]. NFRKB also contains a winged-helix-like domain (residues 370\\u2013495) that does not bind DNA and instead mediates protein\\u2013protein interactions [#3]. The NFRKB\\u2013UCHL5 relationship is reciprocal: UCHL5 deubiquitylates and stabilizes NFRKB against proteasomal degradation, and this stabilization is required for DNA double-strand break resection and homologous recombination repair [#2]. This axis is modulated by the lncRNA DRAIC, which binds UCHL5, weakens its interaction with NFRKB, and thereby promotes NFRKB degradation to restrain gastric cancer cell proliferation and invasion [#5]. NFRKB additionally associates with telomeres in alternative-lengthening-of-telomeres (ALT) cells, where its loss induces telomere dysfunction and reduces PML bodies [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining NFRKB's structural architecture clarified whether it acts directly on DNA or through protein contacts, establishing that its winged-helix-like region serves protein-interaction rather than DNA-binding roles.\",\n      \"evidence\": \"High-throughput X-ray crystallography of residues 370\\u2013495 with a negative DNA-binding assay\",\n      \"pmids\": [\"22984442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of regions outside 370\\u2013495 unresolved\", \"Specific interaction partners of the winged-helix domain not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Bioinformatic identification of a shared DEUBAD domain across NFRKB, ADRM1, and ASXL1 placed NFRKB within a family of UCH37/UCH-L5 regulators, predicting a regulatory link later confirmed structurally.\",\n      \"evidence\": \"Comparative sequence analysis identifying the DEUBAD domain\",\n      \"pmids\": [\"22645167\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no biochemistry on NFRKB\", \"Did not establish direction of regulation (activation vs inhibition)\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Functional epistasis revealed that UCHL5 stabilizes NFRKB and that this stabilization is required for homologous recombination, linking the NFRKB\\u2013UCHL5 pair to DNA double-strand break repair.\",\n      \"evidence\": \"DUB siRNA screen, co-IP, and HR reporter/DSB resection assays in human cells\",\n      \"pmids\": [\"25194926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular role of NFRKB at break sites not defined\", \"Whether INO80 complex integrity is required not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures resolved how NFRKB inhibits UCH37/UCH-L5, showing it blocks the ubiquitin-binding site and disrupts the active site\\u2014the structural basis for its function as a DEUBAD-domain inhibitor.\",\n      \"evidence\": \"Crystal structures of the UCH37\\u2013NFRKB/INO80G DEUBAD complex with mutagenesis and activity assays, replicated across two studies\",\n      \"pmids\": [\"25702872\", \"25702870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrates whose deubiquitylation is blocked not enumerated\", \"How inhibition is relieved in vivo not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying lncRNA DRAIC as a competitor of the UCHL5\\u2013NFRKB interaction showed how NFRKB levels are tuned, connecting NFRKB stability to cancer cell proliferation and metastasis.\",\n      \"evidence\": \"RNA-IP, co-IP, ubiquitination assays, CHX/MG132 chase, and NFRKB-overexpression rescue in gastric cancer cells\",\n      \"pmids\": [\"32351584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct binding interfaces of DRAIC not mapped\", \"Generalizability beyond gastric cancer unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating telomere association in ALT cells extended NFRKB's genome-maintenance role beyond DSB repair to telomere protection.\",\n      \"evidence\": \"Immunostaining/FISH co-localization and siRNA loss-of-function showing telomere dysfunction and reduced PML bodies in U2OS cells\",\n      \"pmids\": [\"34591601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of telomere recruitment unknown\", \"Dependence on UCHL5 or INO80 complex not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NFRKB integrates INO80 chromatin remodeling, UCH-L5 inhibition, and genome maintenance into a unified pathway, and what substrates its inhibition of UCH-L5 protects, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined catalytic substrate set for the NFRKB-inhibited UCH-L5\", \"Mechanistic link between INO80 remodeling and DSB/telomere roles unestablished\", \"Recruitment determinants to chromatin and telomeres unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"INO80 chromatin remodeling complex\"],\n    \"partners\": [\"UCHL5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}