{"gene":"MINDY3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2011,"finding":"C10ORF97 (MINDY3) physically associates with JAB1 (Jun-activating domain-binding protein-1) and blocks JAB1-mediated translocation of p27 from the nucleus to the cytoplasm, thereby causing G1 arrest and suppressing tumor cell growth, migration, and adhesion.","method":"Co-immunoprecipitation (physical association), cell-cycle analysis, overexpression/knockdown with phenotypic readouts (proliferation, anchorage-independent growth, motility), in vivo tumor suppression assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP demonstrating physical association, multiple cellular phenotypes (G1 arrest, growth suppression, motility), and in vivo validation, but single lab and no in vitro reconstitution of the mechanism","pmids":["21499297"],"is_preprint":false},{"year":2026,"finding":"TTC26 acts as a scaffold protein that recruits MINDY3 to its substrate RACK1, facilitating MINDY3-mediated K48-linked deubiquitination of RACK1, thereby stabilizing RACK1 and activating NFATc1 to drive osteoclastogenesis.","method":"Co-immunoprecipitation, Western blotting, in vitro osteoclast differentiation assays, RNA sequencing, protein structural analysis, mouse models (Ttc26 conditional knockout)","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro differentiation assays, and in vivo mouse model in a single lab; deubiquitination linkage type identified but full in vitro reconstitution not explicitly stated in abstract","pmids":["42006908"],"is_preprint":false},{"year":2025,"finding":"The EF-hand domain of MINDY3 is a ubiquitin-binding domain with three distinct binding sites that enables MINDY3 to bind and cleave long K48-linked polyubiquitin chains. The EF-hand domain also binds specifically to the UBL domain of RAD23A and RAD23B (but not other UBL domains), mediates MINDY3 recruitment to DNA damage sites in cells, and allows MINDY3 to form a ternary complex with RAD23A/B and polyubiquitin, suggesting it can deubiquitylate RAD23A/B-bound clients.","method":"Crystal structure of MINDY3 EF-hand:RAD23A UBL domain complex, in vitro ubiquitin-cleavage assays, binding assays with multiple UBL domains, cell-based DNA damage recruitment assay, ternary complex formation assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation, in vitro cleavage assay, binding specificity panel, and cell-based recruitment, all in one rigorous study; preprint not yet peer-reviewed lowers from Strong to Moderate","pmids":["bio_10.1101_2025.07.16.665128"],"is_preprint":true}],"current_model":"MINDY3 is a K48-linked polyubiquitin-preferring deubiquitinase whose atypical EF-hand insertion functions as a ubiquitin-binding domain (with three sites) that enhances cleavage of long polyubiquitin chains and selectively binds the UBL domains of RAD23A/B to recruit MINDY3 to DNA damage sites; in osteoclasts, MINDY3 is scaffolded by TTC26 to deubiquitinate RACK1 (K48-linked), stabilizing RACK1 and activating NFATc1-driven osteoclastogenesis, and separately MINDY3 (as C10ORF97) suppresses cell proliferation by physically associating with JAB1 to block nuclear-to-cytoplasmic translocation of p27."},"narrative":{"mechanistic_narrative":"MINDY3 is a K48-linked polyubiquitin-preferring deubiquitinase that acts on protein stability and cell-cycle control across multiple cellular contexts [PMID:42006908, PMID:bio_10.1101_2025.07.16.665128]. Its catalytic activity toward long K48-linked polyubiquitin chains is potentiated by an atypical EF-hand domain that doubles as a ubiquitin-binding module with three distinct binding sites; this same domain selectively engages the UBL domains of RAD23A and RAD23B, recruits MINDY3 to DNA damage sites, and assembles a ternary complex with RAD23A/B and polyubiquitin, positioning MINDY3 to deubiquitinate RAD23-bound clients [PMID:bio_10.1101_2025.07.16.665128]. In osteoclasts, MINDY3 is delivered to its substrate RACK1 by the scaffold TTC26, where it removes K48-linked chains to stabilize RACK1 and activate NFATc1-driven osteoclastogenesis [PMID:42006908]. Independently, MINDY3 (as C10ORF97) physically associates with JAB1 to block JAB1-mediated nuclear-to-cytoplasmic translocation of p27, producing G1 arrest and suppressing tumor cell growth, migration, and adhesion [PMID:21499297].","teleology":[{"year":2011,"claim":"Before its enzymatic identity was known, MINDY3 (C10ORF97) was placed as a growth suppressor by showing it controls p27 localization, establishing a cell-cycle function for the protein.","evidence":"Co-immunoprecipitation, cell-cycle and proliferation/motility assays, and in vivo tumor suppression in cells","pmids":["21499297"],"confidence":"Medium","gaps":["Mechanism described as physical association without in vitro reconstitution","No link to deubiquitinase activity established at this stage","Single-lab finding without reciprocal structural validation of the JAB1 interaction"]},{"year":2025,"claim":"The structural basis of MINDY3 chain selectivity and recruitment was resolved by showing its EF-hand domain is a three-site ubiquitin-binding module that both enhances cleavage of long K48 chains and specifically binds RAD23A/B UBL domains to target DNA damage sites.","evidence":"Crystal structure of EF-hand:RAD23A UBL complex, in vitro cleavage and UBL-binding specificity panels, and cell-based DNA damage recruitment assays","pmids":["bio_10.1101_2025.07.16.665128"],"confidence":"High","gaps":["Preprint not yet peer-reviewed","Direct deubiquitylation of RAD23A/B-bound clients inferred from ternary complex but not demonstrated on physiological substrates","Functional consequence of DNA damage recruitment on repair outcomes not measured"]},{"year":2026,"claim":"A physiological substrate and recruitment route were defined by showing TTC26 scaffolds MINDY3 onto RACK1 for K48-linked deubiquitination, linking MINDY3 catalysis to NFATc1-driven osteoclastogenesis.","evidence":"Reciprocal Co-IP, Western blotting, in vitro osteoclast differentiation assays, RNA-seq, and Ttc26 conditional knockout mouse models","pmids":["42006908"],"confidence":"Medium","gaps":["Full in vitro reconstitution of MINDY3-mediated RACK1 deubiquitination not explicitly established","How TTC26 scaffolding relates to EF-hand/RAD23-mediated recruitment is unresolved","Single-lab in vivo model"]},{"year":null,"claim":"Whether the distinct functions of MINDY3 — p27/JAB1 cell-cycle control, RAD23-directed DNA damage recruitment, and TTC26/RACK1 osteoclast signaling — represent one unified substrate logic or context-specific adaptor-driven targeting remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No single study integrates the DNA damage, cell-cycle, and osteoclast roles","Catalytic dependence of the p27/JAB1 phenotype on deubiquitinase activity untested","Full complement of physiological MINDY3 substrates undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["RAD23A","RAD23B","TTC26","RACK1","JAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H8M7","full_name":"Ubiquitin carboxyl-terminal hydrolase MINDY-3","aliases":["Dermal papilla-derived protein 5","Deubiquitinating enzyme MINDY-3","Protein CARP"],"length_aa":445,"mass_kda":49.7,"function":"Hydrolase that can remove 'Lys-48'-linked conjugated ubiquitin from proteins","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H8M7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MINDY3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MINDY3","total_profiled":1310},"omim":[{"mim_id":"618408","title":"MINDY LYSINE-48 DEUBIQUITINASE 2; MINDY2","url":"https://www.omim.org/entry/618408"},{"mim_id":"618407","title":"MINDY LYSINE-48 DEUBIQUITINASE 1; MINDY1","url":"https://www.omim.org/entry/618407"},{"mim_id":"611649","title":"MINDY LYSINE-48 DEUBIQUITINASE 3; MINDY3","url":"https://www.omim.org/entry/611649"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MINDY3"},"hgnc":{"alias_symbol":["FLJ13397","CARP","my042","DERP5"],"prev_symbol":["C10orf97","FAM188A"]},"alphafold":{"accession":"Q9H8M7","domains":[{"cath_id":"-","chopping":"1-112_147-195","consensus_level":"medium","plddt":91.2647,"start":1,"end":195},{"cath_id":"1.10.238.10","chopping":"304-368","consensus_level":"high","plddt":92.9777,"start":304,"end":368},{"cath_id":"-","chopping":"377-435","consensus_level":"medium","plddt":91.6039,"start":377,"end":435}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8M7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8M7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8M7-F1-predicted_aligned_error_v6.png","plddt_mean":87.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MINDY3","jax_strain_url":"https://www.jax.org/strain/search?query=MINDY3"},"sequence":{"accession":"Q9H8M7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8M7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8M7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8M7"}},"corpus_meta":[{"pmid":"17652099","id":"PMC_17652099","title":"Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17652099","citation_count":64,"is_preprint":false},{"pmid":"21499297","id":"PMC_21499297","title":"C10ORF97 is a novel tumor-suppressor gene of non-small-cell lung cancer and a functional variant of this gene increases the risk of non-small-cell lung cancer.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21499297","citation_count":5,"is_preprint":false},{"pmid":"41127956","id":"PMC_41127956","title":"Deep eutectic solvent extraction of Tremella fuciformis polysaccharide and the extract's antioxidant activity.","date":"2025","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/41127956","citation_count":2,"is_preprint":false},{"pmid":"39229655","id":"PMC_39229655","title":"CircFAM188A Regulates Autophagy via miR-670-3p and ULK1 in Epithelial Ovarian Carcinoma.","date":"2024","source":"Cancer reports (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/39229655","citation_count":1,"is_preprint":false},{"pmid":"42006908","id":"PMC_42006908","title":"TTC26 scaffolds MINDY3-mediated RACK1 deubiquitination to drive osteoclastogenesis and pathological bone resorption.","date":"2026","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/42006908","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.16.665128","title":"The EF-hand domain of MINDY3 is a Ubiquitin and RAD23 UBL-binding domain","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665128","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5976,"output_tokens":1089,"usd":0.017132,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7624,"output_tokens":1825,"usd":0.041872,"stage2_stop_reason":"end_turn"},"total_usd":0.059004,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"C10ORF97 (MINDY3) physically associates with JAB1 (Jun-activating domain-binding protein-1) and blocks JAB1-mediated translocation of p27 from the nucleus to the cytoplasm, thereby causing G1 arrest and suppressing tumor cell growth, migration, and adhesion.\",\n      \"method\": \"Co-immunoprecipitation (physical association), cell-cycle analysis, overexpression/knockdown with phenotypic readouts (proliferation, anchorage-independent growth, motility), in vivo tumor suppression assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP demonstrating physical association, multiple cellular phenotypes (G1 arrest, growth suppression, motility), and in vivo validation, but single lab and no in vitro reconstitution of the mechanism\",\n      \"pmids\": [\"21499297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TTC26 acts as a scaffold protein that recruits MINDY3 to its substrate RACK1, facilitating MINDY3-mediated K48-linked deubiquitination of RACK1, thereby stabilizing RACK1 and activating NFATc1 to drive osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, in vitro osteoclast differentiation assays, RNA sequencing, protein structural analysis, mouse models (Ttc26 conditional knockout)\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro differentiation assays, and in vivo mouse model in a single lab; deubiquitination linkage type identified but full in vitro reconstitution not explicitly stated in abstract\",\n      \"pmids\": [\"42006908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The EF-hand domain of MINDY3 is a ubiquitin-binding domain with three distinct binding sites that enables MINDY3 to bind and cleave long K48-linked polyubiquitin chains. The EF-hand domain also binds specifically to the UBL domain of RAD23A and RAD23B (but not other UBL domains), mediates MINDY3 recruitment to DNA damage sites in cells, and allows MINDY3 to form a ternary complex with RAD23A/B and polyubiquitin, suggesting it can deubiquitylate RAD23A/B-bound clients.\",\n      \"method\": \"Crystal structure of MINDY3 EF-hand:RAD23A UBL domain complex, in vitro ubiquitin-cleavage assays, binding assays with multiple UBL domains, cell-based DNA damage recruitment assay, ternary complex formation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation, in vitro cleavage assay, binding specificity panel, and cell-based recruitment, all in one rigorous study; preprint not yet peer-reviewed lowers from Strong to Moderate\",\n      \"pmids\": [\"bio_10.1101_2025.07.16.665128\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MINDY3 is a K48-linked polyubiquitin-preferring deubiquitinase whose atypical EF-hand insertion functions as a ubiquitin-binding domain (with three sites) that enhances cleavage of long polyubiquitin chains and selectively binds the UBL domains of RAD23A/B to recruit MINDY3 to DNA damage sites; in osteoclasts, MINDY3 is scaffolded by TTC26 to deubiquitinate RACK1 (K48-linked), stabilizing RACK1 and activating NFATc1-driven osteoclastogenesis, and separately MINDY3 (as C10ORF97) suppresses cell proliferation by physically associating with JAB1 to block nuclear-to-cytoplasmic translocation of p27.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MINDY3 is a K48-linked polyubiquitin-preferring deubiquitinase that acts on protein stability and cell-cycle control across multiple cellular contexts [#1, #2]. Its catalytic activity toward long K48-linked polyubiquitin chains is potentiated by an atypical EF-hand domain that doubles as a ubiquitin-binding module with three distinct binding sites; this same domain selectively engages the UBL domains of RAD23A and RAD23B, recruits MINDY3 to DNA damage sites, and assembles a ternary complex with RAD23A/B and polyubiquitin, positioning MINDY3 to deubiquitinate RAD23-bound clients [#2]. In osteoclasts, MINDY3 is delivered to its substrate RACK1 by the scaffold TTC26, where it removes K48-linked chains to stabilize RACK1 and activate NFATc1-driven osteoclastogenesis [#1]. Independently, MINDY3 (as C10ORF97) physically associates with JAB1 to block JAB1-mediated nuclear-to-cytoplasmic translocation of p27, producing G1 arrest and suppressing tumor cell growth, migration, and adhesion [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Before its enzymatic identity was known, MINDY3 (C10ORF97) was placed as a growth suppressor by showing it controls p27 localization, establishing a cell-cycle function for the protein.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-cycle and proliferation/motility assays, and in vivo tumor suppression in cells\",\n      \"pmids\": [\"21499297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism described as physical association without in vitro reconstitution\",\n        \"No link to deubiquitinase activity established at this stage\",\n        \"Single-lab finding without reciprocal structural validation of the JAB1 interaction\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The structural basis of MINDY3 chain selectivity and recruitment was resolved by showing its EF-hand domain is a three-site ubiquitin-binding module that both enhances cleavage of long K48 chains and specifically binds RAD23A/B UBL domains to target DNA damage sites.\",\n      \"evidence\": \"Crystal structure of EF-hand:RAD23A UBL complex, in vitro cleavage and UBL-binding specificity panels, and cell-based DNA damage recruitment assays\",\n      \"pmids\": [\"bio_10.1101_2025.07.16.665128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Direct deubiquitylation of RAD23A/B-bound clients inferred from ternary complex but not demonstrated on physiological substrates\",\n        \"Functional consequence of DNA damage recruitment on repair outcomes not measured\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A physiological substrate and recruitment route were defined by showing TTC26 scaffolds MINDY3 onto RACK1 for K48-linked deubiquitination, linking MINDY3 catalysis to NFATc1-driven osteoclastogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, Western blotting, in vitro osteoclast differentiation assays, RNA-seq, and Ttc26 conditional knockout mouse models\",\n      \"pmids\": [\"42006908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Full in vitro reconstitution of MINDY3-mediated RACK1 deubiquitination not explicitly established\",\n        \"How TTC26 scaffolding relates to EF-hand/RAD23-mediated recruitment is unresolved\",\n        \"Single-lab in vivo model\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the distinct functions of MINDY3 — p27/JAB1 cell-cycle control, RAD23-directed DNA damage recruitment, and TTC26/RACK1 osteoclast signaling — represent one unified substrate logic or context-specific adaptor-driven targeting remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No single study integrates the DNA damage, cell-cycle, and osteoclast roles\",\n        \"Catalytic dependence of the p27/JAB1 phenotype on deubiquitinase activity untested\",\n        \"Full complement of physiological MINDY3 substrates undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAD23A\", \"RAD23B\", \"TTC26\", \"RACK1\", \"JAB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}