{"gene":"TATDN3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2023,"finding":"TATDN3 exhibits AP (apurinic/apyrimidinic) endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA, both requiring divalent metal cofactors (Mg2+ or Mn2+); certain divalent metals inhibit exonuclease activity while supporting AP endonuclease activity.","method":"In vitro nuclease activity assays with purified recombinant TATDN3, biochemical characterization of metal cofactor requirements","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution of enzymatic activities with purified protein, multiple orthogonal biochemical assays in a single rigorous study","pmids":["36881763"],"is_preprint":false},{"year":2023,"finding":"Active-site residues that differentiate nuclease activities between TATDN1 and TATDN3 were identified; two-metal ion catalysis mechanism is consistent with biochemical and structural data (crystal structure obtained for TATDN1 bound to 2'-deoxyadenosine 5'-monophosphate).","method":"Active-site mutagenesis and crystal structure of TATDN1 (representative of the TATDN1 clade); biochemical comparison with TATDN3","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure and mutagenesis performed primarily on TATDN1; inference to TATDN3 mechanism is biochemically supported but structural data is from the paralog","pmids":["36881763"],"is_preprint":false}],"current_model":"TATDN3 is a divalent metal-dependent nuclease that catalyzes AP endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA via a two-metal ion mechanism, classifying it as a member of an ancient family of AP endonucleases conserved from bacteria to humans."},"narrative":{"mechanistic_narrative":"TATDN3 is a divalent metal-dependent DNA nuclease that catalyzes AP (apurinic/apyrimidinic) endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA, with both activities requiring Mg2+ or Mn2+ cofactors [PMID:36881763]. The two activities are differentially regulated by the metal identity, as certain divalent metals support AP endonuclease cleavage while inhibiting the exonuclease function [PMID:36881763]. Catalysis proceeds through a two-metal ion mechanism, and active-site residues distinguishing the nuclease behavior of TATDN3 from its paralog TATDN1 have been mapped [PMID:36881763]. Beyond this in vitro enzymatic characterization, no cellular pathway, substrate context, or in vivo role for TATDN3 has been established in the available corpus.","teleology":[{"year":2023,"claim":"Whether TATDN3 possesses nuclease activity and on what substrates was unknown; reconstitution with purified protein established it as a metal-dependent enzyme acting on both double- and single-stranded DNA.","evidence":"In vitro nuclease assays with purified recombinant TATDN3 and biochemical characterization of metal cofactor requirements","pmids":["36881763"],"confidence":"High","gaps":["No in vivo or cellular substrate or pathway context established","Physiological relevance of the AP endonuclease and exonuclease activities not demonstrated","Subcellular localization not determined"]},{"year":2023,"claim":"How TATDN3 achieves catalysis and how it differs from its paralog was unclear; mutagenesis and a paralog crystal structure pointed to a two-metal ion mechanism and identified residues differentiating TATDN1 from TATDN3.","evidence":"Active-site mutagenesis and crystal structure of the paralog TATDN1 bound to dAMP, with biochemical comparison to TATDN3","pmids":["36881763"],"confidence":"Medium","gaps":["Structural data derive from the paralog TATDN1, not TATDN3 itself","No experimental structure of TATDN3 with substrate or metal","Mechanistic inference to TATDN3 rests on biochemical analogy"]},{"year":null,"claim":"The cellular and physiological role of TATDN3 — its DNA repair or processing pathway, in vivo substrates, regulation, and localization — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cellular phenotype or loss-of-function study in the corpus","No identified pathway partners or recruitment mechanism","No demonstrated role in DNA repair in cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q17R31","full_name":"Deoxyribonuclease TATDN3","aliases":["DNA-(apurinic or apyrimidinic site) endonuclease TATDN3","TatD DNase domain containing 3"],"length_aa":274,"mass_kda":30.3,"function":"Exhibits 3'-exonuclease and apurinic/apyrimidinic (AP) endonuclease activities (in vitro). Show preferential AP endonuclease activity on double-stranded DNA substrates and 3'- exonuclease activity on single-stranded DNA","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q17R31/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TATDN3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000203705","cell_line_id":"CID000801","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ARFGEF1","stoichiometry":0.2},{"gene":"MSH6","stoichiometry":0.2},{"gene":"HSPA2","stoichiometry":0.2},{"gene":"RAD50","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000801","total_profiled":1310},"omim":[{"mim_id":"621462","title":"TatD DNase DOMAIN-CONTAINING PROTEIN 3; TATDN3","url":"https://www.omim.org/entry/621462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TATDN3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q17R31","domains":[{"cath_id":"3.20.20.140","chopping":"9-274","consensus_level":"high","plddt":97.1261,"start":9,"end":274}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q17R31","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q17R31-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q17R31-F1-predicted_aligned_error_v6.png","plddt_mean":96.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TATDN3","jax_strain_url":"https://www.jax.org/strain/search?query=TATDN3"},"sequence":{"accession":"Q17R31","fasta_url":"https://rest.uniprot.org/uniprotkb/Q17R31.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q17R31/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q17R31"}},"corpus_meta":[{"pmid":"36881763","id":"PMC_36881763","title":"Human and bacterial TatD enzymes exhibit apurinic/apyrimidinic (AP) endonuclease activity.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36881763","citation_count":13,"is_preprint":false},{"pmid":"41528614","id":"PMC_41528614","title":"Mendelian randomization analysis of PKD1 in endometrial cancer and comparative multi-cancer study with renal cell carcinoma.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41528614","citation_count":0,"is_preprint":false},{"pmid":"40032003","id":"PMC_40032003","title":"Extracellular TatD from Listeria monocytogenes displays DNase activity and contributes to biofilm dispersion.","date":"2025","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40032003","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3918,"output_tokens":578,"usd":0.010212,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6902,"output_tokens":1211,"usd":0.032392,"stage2_stop_reason":"end_turn"},"total_usd":0.042604,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"TATDN3 exhibits AP (apurinic/apyrimidinic) endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA, both requiring divalent metal cofactors (Mg2+ or Mn2+); certain divalent metals inhibit exonuclease activity while supporting AP endonuclease activity.\",\n      \"method\": \"In vitro nuclease activity assays with purified recombinant TATDN3, biochemical characterization of metal cofactor requirements\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution of enzymatic activities with purified protein, multiple orthogonal biochemical assays in a single rigorous study\",\n      \"pmids\": [\"36881763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Active-site residues that differentiate nuclease activities between TATDN1 and TATDN3 were identified; two-metal ion catalysis mechanism is consistent with biochemical and structural data (crystal structure obtained for TATDN1 bound to 2'-deoxyadenosine 5'-monophosphate).\",\n      \"method\": \"Active-site mutagenesis and crystal structure of TATDN1 (representative of the TATDN1 clade); biochemical comparison with TATDN3\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure and mutagenesis performed primarily on TATDN1; inference to TATDN3 mechanism is biochemically supported but structural data is from the paralog\",\n      \"pmids\": [\"36881763\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TATDN3 is a divalent metal-dependent nuclease that catalyzes AP endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA via a two-metal ion mechanism, classifying it as a member of an ancient family of AP endonucleases conserved from bacteria to humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TATDN3 is a divalent metal-dependent DNA nuclease that catalyzes AP (apurinic/apyrimidinic) endonuclease activity on double-stranded DNA and 3'-5' exonuclease activity on single-stranded DNA, with both activities requiring Mg2+ or Mn2+ cofactors [#0]. The two activities are differentially regulated by the metal identity, as certain divalent metals support AP endonuclease cleavage while inhibiting the exonuclease function [#0]. Catalysis proceeds through a two-metal ion mechanism, and active-site residues distinguishing the nuclease behavior of TATDN3 from its paralog TATDN1 have been mapped [#1]. Beyond this in vitro enzymatic characterization, no cellular pathway, substrate context, or in vivo role for TATDN3 has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether TATDN3 possesses nuclease activity and on what substrates was unknown; reconstitution with purified protein established it as a metal-dependent enzyme acting on both double- and single-stranded DNA.\",\n      \"evidence\": \"In vitro nuclease assays with purified recombinant TATDN3 and biochemical characterization of metal cofactor requirements\",\n      \"pmids\": [\"36881763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo or cellular substrate or pathway context established\",\n        \"Physiological relevance of the AP endonuclease and exonuclease activities not demonstrated\",\n        \"Subcellular localization not determined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How TATDN3 achieves catalysis and how it differs from its paralog was unclear; mutagenesis and a paralog crystal structure pointed to a two-metal ion mechanism and identified residues differentiating TATDN1 from TATDN3.\",\n      \"evidence\": \"Active-site mutagenesis and crystal structure of the paralog TATDN1 bound to dAMP, with biochemical comparison to TATDN3\",\n      \"pmids\": [\"36881763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural data derive from the paralog TATDN1, not TATDN3 itself\",\n        \"No experimental structure of TATDN3 with substrate or metal\",\n        \"Mechanistic inference to TATDN3 rests on biochemical analogy\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cellular and physiological role of TATDN3 — its DNA repair or processing pathway, in vivo substrates, regulation, and localization — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cellular phenotype or loss-of-function study in the corpus\",\n        \"No identified pathway partners or recruitment mechanism\",\n        \"No demonstrated role in DNA repair in cells\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}