{"gene":"PF3D7_0308000","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":1996,"finding":"PfDNA Pol delta (the large subunit encoded by PF3D7_0308000 or its immediate partner) protein accumulates in trophozoites and persists in schizonts, with promoter activity absent in rings but present in trophozoites and schizonts, indicating stage-specific transcriptional regulation; its coordinated activity with PfPCNA is required for DNA replication.","method":"Western blot with antisera against PfDNA Pol delta on synchronised parasite extracts; nuclear run-on analysis for promoter activity","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein detection and nuclear run-on in synchronised parasites, single lab, two orthogonal methods","pmids":["8855554"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"The 5' flanking region of the P. falciparum DNA polymerase delta gene (PF3D7_0308000) contains regulatory elements: promoter-proximal sequences repress expression, the ATG-proximal 5' UTR is required together with the promoter for reporter activity, a central portion of the 5' UTR has a positive effect on expression, and disruption of a homopolymeric (dA:dT) tract adjacent to the main transcription start site both derepresses gene expression and reduces intrinsic DNA curvature.","method":"Deletion and mutational analysis of 5' flanking sequences driving a luciferase reporter in P. falciparum transfection assays","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive deletion/mutagenesis with reporter assay, single lab, multiple sequence elements tested","pmids":["12076766"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Computational protein-protein interaction analysis and AlphaFold modelling identified PF3D7_0308000 (DNA polymerase delta small subunit) as an interaction partner of the P. falciparum surface protein P113, with the helical-rich domain of P113 (residues 311-679) predicted as the critical binding region for PF3D7_0308000, and key P113 interaction residues mapped to Asp475, Arg381, Lys386, Asn390, Asp392, and Lys533.","method":"STRING protein-protein interaction analysis and AlphaFold structural prediction; no in vitro or in vivo binding validation reported","journal":"Acta crystallographica. Section D, Structural biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only (STRING + AlphaFold), no experimental binding validation performed","pmids":["40192714"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0308000 (DNA polymerase delta small subunit) is expressed in a stage-specific manner in P. falciparum, accumulating at the trophozoite/schizont stage under transcriptional control involving (dA:dT)-rich promoter elements and a regulatory 5' UTR, where it acts coordinately with PfPCNA for nuclear DNA replication; a computational study additionally predicts an interaction with the surface-anchoring protein P113, but this has not been experimentally validated."},"narrative":{"mechanistic_narrative":"PF3D7_0308000 encodes a DNA polymerase delta subunit implicated in nuclear DNA replication in Plasmodium falciparum, where its expression is tightly coupled to the parasite's intraerythrocytic cell cycle [PMID:8855554]. The protein is absent from rings and accumulates at the trophozoite and schizont stages, coincident with genome replication, and its activity is required coordinately with PfPCNA for DNA replication [PMID:8855554]. This stage-specific pattern is enforced transcriptionally: the gene's 5' flanking region combines promoter-proximal repressive sequences with a 5' UTR that is required for expression, and a homopolymeric (dA:dT) tract adjacent to the main transcription start site both restrains expression and contributes to intrinsic DNA curvature, since disrupting it derepresses the gene and reduces curvature [PMID:12076766]. Beyond this transcriptional and replicative context, no biochemical characterization of the protein itself is available in the corpus; a predicted interaction with the surface protein P113 rests only on computational modelling without experimental validation [PMID:40192714].","teleology":[{"year":1996,"claim":"Establishing when a replicative DNA polymerase acts during the parasite cell cycle was needed to place it in the replication program; detection showed the protein accumulates specifically at replicative stages and functions with PfPCNA.","evidence":"Western blot with anti-PfDNA Pol delta antisera on synchronised parasites plus nuclear run-on promoter analysis","pmids":["8855554"],"confidence":"Medium","gaps":["Does not resolve which polypeptide (large versus small subunit) the antisera detect, so the assignment to PF3D7_0308000 specifically is ambiguous","No direct enzymatic or reconstitution assay of the PF3D7_0308000 product","Mechanism of PfPCNA coordination not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"claim":"How stage-specific expression is encoded was unknown; dissection of the 5' flanking region defined discrete repressive and activating elements and linked a (dA:dT) tract to both expression control and local DNA structure.","evidence":"Deletion and mutational analysis of 5' flanking sequences driving a luciferase reporter in P. falciparum transfection assays","pmids":["12076766"],"confidence":"Medium","gaps":["Trans-acting factors binding these elements not identified","Reporter assays do not confirm the endogenous protein-level consequences","Mechanistic link between DNA curvature and transcriptional output not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether the subunit engages partners outside the replication machinery was tested computationally, predicting a binding interface with the surface protein P113.","evidence":"STRING protein-protein interaction analysis and AlphaFold structural modelling; no in vitro or in vivo binding validation","pmids":["40192714"],"confidence":"Low","gaps":["Purely computational prediction with no experimental binding validation","No demonstrated co-localization or functional consequence of a P113 interaction","Biological rationale for a replication subunit binding a surface protein is unestablished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Direct biochemical and structural characterization of the PF3D7_0308000 gene product—its catalytic or accessory role within DNA polymerase delta and validated protein partners—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted polymerase delta complex or subunit stoichiometry defined for PF3D7_0308000","No experimentally validated interactome","No loss-of-function/essentiality data for PF3D7_0308000 in the corpus"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["DNA polymerase delta (functional coordination with PfPCNA) [#0]"],"partners":["PFPCNA (COORDINATED ACTIVITY IN DNA REPLICATION) [#0]","P113 (COMPUTATIONALLY PREDICTED, UNVALIDATED) [#2]"],"other_free_text":["Stage-specific expression: absent in rings, accumulates in trophozoites and persists in schizonts [#0]","Transcriptional regulation via 5' flanking region with repressive promoter-proximal sequences, an expression-required 5' UTR, and a (dA:dT) homopolymeric tract linked to expression control and DNA curvature [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15926203","id":"PMC_15926203","title":"The plastidic DNA replication enzyme complex of Plasmodium falciparum.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15926203","citation_count":68,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3088783","id":"PMC_3088783","title":"Rapid repeated DNA replication during microgametogenesis and DNA synthesis in young zygotes of Plasmodium berghei.","date":"1986","source":"Transactions of the Royal Society of Tropical Medicine and Hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/3088783","citation_count":61,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2440713","id":"PMC_2440713","title":"Plasmodium species: flow cytometry and microfluorometry assessments of DNA content and synthesis.","date":"1987","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2440713","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3283664","id":"PMC_3283664","title":"DNA synthesis in gametocytes of Plasmodium falciparum.","date":"1988","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/3283664","citation_count":47,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8855554","id":"PMC_8855554","title":"Stage specific expression of proliferating cell nuclear antigen and DNA polymerase delta from Plasmodium falciparum.","date":"1996","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8855554","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA","PfDNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"1857384","id":"PMC_1857384","title":"Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA.","date":"1991","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/1857384","citation_count":29,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27338018","id":"PMC_27338018","title":"Replication and maintenance of the Plasmodium falciparum apicoplast genome.","date":"2016","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/27338018","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12076766","id":"PMC_12076766","title":"Positive and negative effects of deletions and mutations within the 5' flanking sequences of Plasmodium falciparum DNA polymerase delta.","date":"2002","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/12076766","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"1903844","id":"PMC_1903844","title":"Purification and characterization of DNA polymerases from Plasmodium berghei.","date":"1991","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/1903844","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40192714","id":"PMC_40192714","title":"The crystal structure of an uncharacterized domain of P113 from Plasmodium falciparum.","date":"2025","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/40192714","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA polymerase delta small subunit"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6485,"output_tokens":992,"usd":0.017167,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5704,"output_tokens":1913,"usd":0.038172,"stage2_stop_reason":"end_turn"},"total_usd":0.055339,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PfDNA Pol delta (the large subunit encoded by PF3D7_0308000 or its immediate partner) protein accumulates in trophozoites and persists in schizonts, with promoter activity absent in rings but present in trophozoites and schizonts, indicating stage-specific transcriptional regulation; its coordinated activity with PfPCNA is required for DNA replication.\",\n      \"method\": \"Western blot with antisera against PfDNA Pol delta on synchronised parasite extracts; nuclear run-on analysis for promoter activity\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein detection and nuclear run-on in synchronised parasites, single lab, two orthogonal methods\",\n      \"pmids\": [\"8855554\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The 5' flanking region of the P. falciparum DNA polymerase delta gene (PF3D7_0308000) contains regulatory elements: promoter-proximal sequences repress expression, the ATG-proximal 5' UTR is required together with the promoter for reporter activity, a central portion of the 5' UTR has a positive effect on expression, and disruption of a homopolymeric (dA:dT) tract adjacent to the main transcription start site both derepresses gene expression and reduces intrinsic DNA curvature.\",\n      \"method\": \"Deletion and mutational analysis of 5' flanking sequences driving a luciferase reporter in P. falciparum transfection assays\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive deletion/mutagenesis with reporter assay, single lab, multiple sequence elements tested\",\n      \"pmids\": [\"12076766\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Computational protein-protein interaction analysis and AlphaFold modelling identified PF3D7_0308000 (DNA polymerase delta small subunit) as an interaction partner of the P. falciparum surface protein P113, with the helical-rich domain of P113 (residues 311-679) predicted as the critical binding region for PF3D7_0308000, and key P113 interaction residues mapped to Asp475, Arg381, Lys386, Asn390, Asp392, and Lys533.\",\n      \"method\": \"STRING protein-protein interaction analysis and AlphaFold structural prediction; no in vitro or in vivo binding validation reported\",\n      \"journal\": \"Acta crystallographica. Section D, Structural biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only (STRING + AlphaFold), no experimental binding validation performed\",\n      \"pmids\": [\"40192714\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0308000 (DNA polymerase delta small subunit) is expressed in a stage-specific manner in P. falciparum, accumulating at the trophozoite/schizont stage under transcriptional control involving (dA:dT)-rich promoter elements and a regulatory 5' UTR, where it acts coordinately with PfPCNA for nuclear DNA replication; a computational study additionally predicts an interaction with the surface-anchoring protein P113, but this has not been experimentally validated.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0308000 encodes a DNA polymerase delta subunit implicated in nuclear DNA replication in Plasmodium falciparum, where its expression is tightly coupled to the parasite's intraerythrocytic cell cycle [#0]. The protein is absent from rings and accumulates at the trophozoite and schizont stages, coincident with genome replication, and its activity is required coordinately with PfPCNA for DNA replication [#0]. This stage-specific pattern is enforced transcriptionally: the gene's 5' flanking region combines promoter-proximal repressive sequences with a 5' UTR that is required for expression, and a homopolymeric (dA:dT) tract adjacent to the main transcription start site both restrains expression and contributes to intrinsic DNA curvature, since disrupting it derepresses the gene and reduces curvature [#1]. Beyond this transcriptional and replicative context, no biochemical characterization of the protein itself is available in the corpus; a predicted interaction with the surface protein P113 rests only on computational modelling without experimental validation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing when a replicative DNA polymerase acts during the parasite cell cycle was needed to place it in the replication program; detection showed the protein accumulates specifically at replicative stages and functions with PfPCNA.\",\n      \"evidence\": \"Western blot with anti-PfDNA Pol delta antisera on synchronised parasites plus nuclear run-on promoter analysis\",\n      \"pmids\": [\"8855554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not resolve which polypeptide (large versus small subunit) the antisera detect, so the assignment to PF3D7_0308000 specifically is ambiguous\",\n        \"No direct enzymatic or reconstitution assay of the PF3D7_0308000 product\",\n        \"Mechanism of PfPCNA coordination not defined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"How stage-specific expression is encoded was unknown; dissection of the 5' flanking region defined discrete repressive and activating elements and linked a (dA:dT) tract to both expression control and local DNA structure.\",\n      \"evidence\": \"Deletion and mutational analysis of 5' flanking sequences driving a luciferase reporter in P. falciparum transfection assays\",\n      \"pmids\": [\"12076766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Trans-acting factors binding these elements not identified\",\n        \"Reporter assays do not confirm the endogenous protein-level consequences\",\n        \"Mechanistic link between DNA curvature and transcriptional output not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether the subunit engages partners outside the replication machinery was tested computationally, predicting a binding interface with the surface protein P113.\",\n      \"evidence\": \"STRING protein-protein interaction analysis and AlphaFold structural modelling; no in vitro or in vivo binding validation\",\n      \"pmids\": [\"40192714\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Purely computational prediction with no experimental binding validation\",\n        \"No demonstrated co-localization or functional consequence of a P113 interaction\",\n        \"Biological rationale for a replication subunit binding a surface protein is unestablished\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Direct biochemical and structural characterization of the PF3D7_0308000 gene product—its catalytic or accessory role within DNA polymerase delta and validated protein partners—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted polymerase delta complex or subunit stoichiometry defined for PF3D7_0308000\",\n        \"No experimentally validated interactome\",\n        \"No loss-of-function/essentiality data for PF3D7_0308000 in the corpus\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003887\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006260\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"DNA polymerase delta (functional coordination with PfPCNA) [#0]\"\n    ],\n    \"partners\": [\n      \"PfPCNA (coordinated activity in DNA replication) [#0]\",\n      \"P113 (computationally predicted, unvalidated) [#2]\"\n    ],\n    \"other_free_text\": [\n      \"Stage-specific expression: absent in rings, accumulates in trophozoites and persists in schizonts [#0]\",\n      \"Transcriptional regulation via 5' flanking region with repressive promoter-proximal sequences, an expression-required 5' UTR, and a (dA:dT) homopolymeric tract linked to expression control and DNA curvature [#1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0308000","name":null,"product":"DNA polymerase delta small subunit, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0406300","name":null,"product":"DNA polymerase delta small subunit, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0834700","name":null,"product":"DNA polymerase delta small subunit, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}