{"gene":"PF3D7_1107400","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2003,"finding":"PfRad51 (PF3D7_1107400) encodes a 351 amino acid polypeptide sharing 66–75% sequence identity within the catalytic region with Rad51 from human, yeast, and other protozoan parasites. Its transcript and protein are up-regulated in intra-erythrocytic P. falciparum cultures in response to the DNA damaging agent methyl methanesulfonate (MMS), implicating it in recombinational DNA repair.","method":"Gene identification, sequence analysis, and expression analysis (RT-PCR, Western blot) of MMS-treated P. falciparum cultures","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, expression up-regulation documented by two orthogonal methods (transcript and protein), but no in vitro biochemical activity demonstrated in this paper","pmids":["14527521"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"PfRad51 (PF3D7_1107400) exhibits ATPase activity and promotes DNA strand exchange in vitro. PfRad54 accelerates PfRad51-mediated pairing between ssDNA and homologous linear dsDNA in the presence of CaCl2. PfRPA1L (a replication protein A homologue) stimulates PfRad51-mediated homologous pairing and strand exchange, while PfRPA1S negatively regulates PfRPA1L activity in a dose-dependent manner. In vivo, PfRad51 transcript and protein are up-regulated upon MMS-induced DNA damage.","method":"In vitro ATPase assay, in vitro strand exchange assay with recombinant proteins, comet assay for in vivo DNA damage, RT-PCR and Western blot for expression","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of ATPase and strand exchange activities with multiple recombinant protein partners, plus in vivo corroboration by comet assay and expression data, single lab","pmids":["23631919"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"A dominant negative mutant of PfRad51 (PF3D7_1107400), PfRad51(K143R), when expressed in Plasmodium berghei, abolishes DSB repair as shown by hypersensitivity to DNA-damaging agents. Mice infected with mutant parasites lived significantly longer with markedly reduced parasite burden. In a yeast surrogate model, PfRad51(K143R) completely inhibited DNA repair, gene conversion, and gene targeting. Biochemically, very low levels of mutant protein were sufficient to disrupt wild-type PfRad51 activity, consistent with a dominant negative mechanism. Homologous recombination (HR) was established as the most important DSB repair pathway in Plasmodium.","method":"Dominant negative mutagenesis (K143R), transgenic P. berghei line, DNA damage hypersensitivity assay, mouse infection model, yeast surrogate genetic assay, in vitro biochemical disruption assay","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transgenic parasite, mouse model, yeast genetics, biochemistry), active-site mutagenesis, clear phenotypic readouts","pmids":["25145341"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Based on the crystal structure of the human BRC4-RAD51 complex, sequence fingerprint analysis predicts that the Plasmodium RAD51 orthologue (PF3D7_1107400) retains the interaction interface required for binding BRC repeat motifs of BRCA2, whereas yeast and archaeal/bacterial RAD51 orthologues and human RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, DMC1) do not fulfil the criteria. A BRCA2 homologue containing BRC repeats was identified in two Plasmodium species.","method":"Crystal structure of human BRC4-RAD51 complex used to define interaction fingerprints; comparative sequence analysis applied to Plasmodium RAD51","journal":"DNA repair","confidence":"Low","confidence_rationale":"Tier 4 / Weak — interaction prediction is computational/structural inference from the human complex; no direct biochemical validation of Plasmodium RAD51–BRCA2 interaction was performed","pmids":["12967658"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"The small molecule B02 docks with high affinity to the predicted tertiary structure of PfRad51 (PF3D7_1107400), blocks its ATPase and strand-exchange activities in vitro, abrogates formation of PfRad51 foci on damaged DNA, and inhibits P. falciparum growth (IC50 8 µM in 3D7, 3 µM in Dd2). B02 synergizes with artemisinin and chloroquine (reducing their IC50 values by 15- and 8-fold, respectively) and causes accumulation of unrepaired parasitic DNA. Disruption of homomeric PfRad51 interactions was proposed as the mechanism, consistent with B02 blocking filament formation.","method":"In silico docking, in vitro ATPase assay, in vitro strand exchange assay, immunofluorescence microscopy of PfRad51 foci, parasite growth inhibition assay, drug synergy assay, DNA damage accumulation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal in vitro biochemical assays (ATPase, strand exchange) combined with cellular imaging and parasite growth readouts in a single rigorous study; single lab","pmids":["30936202"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2016,"finding":"In P. falciparum, homologous recombination (HR) and de novo telomere addition compete to repair DSBs in subtelomeric regions, with the pathway used determined by the DNA sequences immediately surrounding the break. Both pathways were observed in response to spontaneous and experimentally induced DSBs, demonstrating that HR (in which PfRad51 participates) is active in repairing DSBs within subtelomeric regions.","method":"Single-molecule real-time (SMRT) sequencing of subtelomeric repair products from spontaneous and induced DSBs in P. falciparum culture","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SMRT sequencing provides direct molecular evidence of repair products; HR pathway involvement inferred from product sequences without direct disruption of PfRad51 in this study","pmids":["28790200"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PfRad51 (PF3D7_1107400) interacts with PfExomit2, a mitochondria-localised exonuclease, in pull-down assays, suggesting that PfRad51 is a component of the mitochondrial double-strand break repair (DSBR) pathway in P. falciparum.","method":"Pull-down assay with recombinant proteins; immunofluorescence localization of interacting partners","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down assay, single lab, no functional validation of the PfRad51–PfExomit2 interaction beyond physical association","pmids":["41243319"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Knockout of PfRad51 (PF3D7_1107400) in P. falciparum causes uniform hypersensitivity to irradiation across the erythrocytic cell cycle. PfRad51 is essential for HR-mediated repair of targeted DSBs in the conserved core genome. In contrast, when DSBs are induced in subtelomeric regions, a Rad51-independent, homology-directed repair pathway operates, indicating that PfRad51 is dispensable for subtelomeric DSB repair.","method":"Genetic knockout (PfRad51Δ), irradiation hypersensitivity assay across the cell cycle, targeted DSB induction with sequencing of repair products","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined phenotypic readouts (irradiation sensitivity, directed DSB repair outcomes), multiple assays, single lab","pmids":["41277688"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Knockout of PfRad51 (PF3D7_1107400) in P. falciparum causes uniform irradiation hypersensitivity across the erythrocytic cycle and is essential for HR-mediated repair in the core genome, while a Rad51-independent homology-directed repair pathway operates in subtelomeric regions (preprint version of the peer-reviewed paper).","method":"Genetic knockout, irradiation sensitivity assay, targeted DSB repair sequencing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint counterpart of peer-reviewed finding; consistent results, single lab; downgraded from High because preprint status","pmids":["40667286"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfRad51 (PF3D7_1107400) is the Plasmodium falciparum RecA/Rad51 recombinase that exhibits ATPase activity, catalyses ATP-dependent DNA strand exchange in vitro, and is the primary driver of homologous recombination (HR)-mediated repair of double-strand breaks (DSBs) in the parasite core genome; its activity is stimulated by PfRad54 and PfRPA1L, negatively modulated by PfRPA1S, and its dominant-negative K143R mutation or small-molecule inhibition (B02) abolishes DSB repair and reduces parasite survival, while subtelomeric DSBs are repaired by a PfRad51-independent, homology-directed pathway."},"narrative":{"mechanistic_narrative":"PF3D7_1107400 (PfRad51) is the RecA/Rad51-family recombinase that drives homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) in Plasmodium falciparum, and its transcript and protein are induced upon MMS-induced DNA damage [PMID:14527521, PMID:23631919]. Biochemically, recombinant PfRad51 hydrolyzes ATP and catalyzes ATP-dependent DNA strand exchange in vitro; this activity is accelerated by PfRad54 and stimulated by the replication protein A homologue PfRPA1L, while PfRPA1S negatively modulates PfRPA1L in a dose-dependent manner [PMID:23631919]. The catalytic requirement is demonstrated by the K143R active-site mutant, which acts dominant-negatively to abolish DSB repair, gene conversion, and gene targeting, establishing HR as the principal DSB repair pathway in Plasmodium [PMID:25145341]. Genetic knockout confirms that PfRad51 is essential for HR-mediated repair of DSBs in the conserved core genome and produces uniform irradiation hypersensitivity across the erythrocytic cycle, whereas subtelomeric DSBs are repaired by a PfRad51-independent, homology-directed pathway [PMID:41277688]. Small-molecule inhibition by B02 blocks PfRad51 ATPase and strand-exchange activities, abrogates damage-induced PfRad51 foci, causes accumulation of unrepaired DNA, and inhibits parasite growth in synergy with artemisinin and chloroquine, consistent with disruption of homomeric filament formation [PMID:30936202]. Beyond these findings, PfRad51's interaction with the BRCA2 BRC-repeat interface [PMID:12967658] and with the mitochondrial exonuclease PfExomit2 [PMID:41243319] have not been experimentally validated beyond structural prediction and a single pull-down, respectively.","teleology":[{"year":2003,"claim":"Whether Plasmodium encodes a bona fide Rad51 recombinase and whether it participates in damage responses was unknown; identification of a Rad51 orthologue induced by a DNA-damaging agent placed PF3D7_1107400 in recombinational repair.","evidence":"Gene identification, sequence analysis, and RT-PCR/Western blot of MMS-treated P. falciparum cultures","pmids":["14527521"],"confidence":"Medium","gaps":["No in vitro recombinase activity demonstrated","Direct role in DSB repair not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Whether PfRad51 could engage a BRCA2-type mediator was addressed computationally, predicting the parasite orthologue retains the BRC-repeat interaction interface unlike other family members.","evidence":"Structural fingerprint analysis from the human BRC4-RAD51 crystal structure applied to Plasmodium RAD51 sequence","pmids":["12967658"],"confidence":"Low","gaps":["Purely computational inference; no biochemical validation of a PfRad51-BRCA2 interaction","No demonstration that a Plasmodium BRC repeat binds PfRad51"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"The catalytic activity of PfRad51 and its regulation were undefined; in vitro reconstitution established ATPase and strand-exchange activity and identified stimulatory (PfRad54, PfRPA1L) and inhibitory (PfRPA1S) partners.","evidence":"In vitro ATPase and strand-exchange assays with recombinant proteins, comet assay, and expression analysis in P. falciparum","pmids":["23631919"],"confidence":"High","gaps":["Partner interactions shown biochemically but not validated in vivo","Stoichiometry and filament architecture not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Whether PfRad51 catalytic function is required for parasite DSB repair and survival was answered by an active-site dominant-negative mutant that abolished repair and reduced parasite burden, establishing HR as the dominant DSB repair route.","evidence":"K143R dominant-negative mutagenesis in transgenic P. berghei, mouse infection model, yeast surrogate genetics, and in vitro disruption assay","pmids":["25145341"],"confidence":"High","gaps":["Dominant-negative rather than clean loss-of-function in P. falciparum","Contribution of specific partners in vivo not dissected"],"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"How subtelomeric DSBs are repaired was probed by sequencing repair products, showing HR competes with de novo telomere addition and that pathway choice is dictated by local sequence.","evidence":"SMRT sequencing of subtelomeric repair products from spontaneous and induced DSBs in P. falciparum","pmids":["28790200"],"confidence":"Medium","gaps":["HR involvement inferred from product sequences without direct PfRad51 disruption","Exact PfRad51 dependence at subtelomeres not tested here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Whether PfRad51 is druggable was tested with B02, which blocked its enzymatic activities and foci formation, killed parasites, and synergized with front-line antimalarials, nominating PfRad51 as a chemotherapeutic target.","evidence":"In silico docking, in vitro ATPase and strand-exchange assays, immunofluorescence of PfRad51 foci, growth inhibition and drug synergy assays in P. falciparum 3D7 and Dd2","pmids":["30936202"],"confidence":"High","gaps":["Filament-disruption mechanism proposed but not structurally confirmed","B02 selectivity for PfRad51 versus host RAD51 not established"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2025,"claim":"Whether PfRad51 is genuinely essential for HR and whether all DSBs depend on it was resolved by knockout, showing it is required for core-genome HR and uniform irradiation resistance but dispensable for a distinct subtelomeric homology-directed pathway.","evidence":"PfRad51 genetic knockout, irradiation hypersensitivity across the erythrocytic cycle, and targeted DSB repair-product sequencing in P. falciparum (peer-reviewed; also as bioRxiv preprint)","pmids":["41277688","40667286"],"confidence":"High","gaps":["Molecular identity of the Rad51-independent subtelomeric pathway not defined","Mechanistic basis of pathway partitioning by genomic region unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether PfRad51 acts beyond nuclear HR was raised by a physical interaction with a mitochondrial exonuclease, hinting at a mitochondrial DSB repair role.","evidence":"Pull-down assay with recombinant PfExomit2 and immunofluorescence localization in P. falciparum","pmids":["41243319"],"confidence":"Low","gaps":["Single pull-down without reciprocal or functional validation","No evidence PfRad51 localizes to or acts within mitochondria"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The molecular identity of the PfRad51-independent subtelomeric homology-directed repair machinery, and whether PfRad51 has a bona fide functional role in mitochondrial DSB repair, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Effectors of Rad51-independent subtelomeric repair unidentified","Functional consequence of PfExomit2 interaction untested","In vivo relevance of BRCA2/BRC-repeat prediction unconfirmed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFRAD54 (ACCELERATES PFRAD51-MEDIATED HOMOLOGOUS PAIRING) [#1]","PFRPA1L (STIMULATES PFRAD51 STRAND EXCHANGE) [#1]","PFRPA1S (NEGATIVELY REGULATES PFRPA1L) [#1]","PFEXOMIT2 (MITOCHONDRIAL EXONUCLEASE; PHYSICAL PULL-DOWN INTERACTION, UNVALIDATED) [#6]"],"other_free_text":["K143R active-site substitution acts as a dominant-negative, abolishing DSB repair, gene conversion, and gene targeting [#2]","Small-molecule inhibitor B02 blocks ATPase and strand-exchange activity, damage-induced foci formation, and parasite growth, synergizing with artemisinin and chloroquine [#4]","Essential for HR repair of core-genome DSBs but dispensable for a Rad51-independent, homology-directed subtelomeric repair pathway [#7]","BRCA2 BRC-repeat interaction interface predicted by structural fingerprint analysis but not experimentally validated [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"10645945","id":"PMC_10645945","title":"The bacterial replicative helicase DnaB evolved from a RecA duplication.","date":"2000","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/10645945","citation_count":162,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAD51"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12967658","id":"PMC_12967658","title":"Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer.","date":"2003","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/12967658","citation_count":100,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAD51"],"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 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Its transcript and protein are up-regulated in intra-erythrocytic P. falciparum cultures in response to the DNA damaging agent methyl methanesulfonate (MMS), implicating it in recombinational DNA repair.\",\n      \"method\": \"Gene identification, sequence analysis, and expression analysis (RT-PCR, Western blot) of MMS-treated P. falciparum cultures\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, expression up-regulation documented by two orthogonal methods (transcript and protein), but no in vitro biochemical activity demonstrated in this paper\",\n      \"pmids\": [\"14527521\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PfRad51 (PF3D7_1107400) exhibits ATPase activity and promotes DNA strand exchange in vitro. PfRad54 accelerates PfRad51-mediated pairing between ssDNA and homologous linear dsDNA in the presence of CaCl2. PfRPA1L (a replication protein A homologue) stimulates PfRad51-mediated homologous pairing and strand exchange, while PfRPA1S negatively regulates PfRPA1L activity in a dose-dependent manner. In vivo, PfRad51 transcript and protein are up-regulated upon MMS-induced DNA damage.\",\n      \"method\": \"In vitro ATPase assay, in vitro strand exchange assay with recombinant proteins, comet assay for in vivo DNA damage, RT-PCR and Western blot for expression\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of ATPase and strand exchange activities with multiple recombinant protein partners, plus in vivo corroboration by comet assay and expression data, single lab\",\n      \"pmids\": [\"23631919\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A dominant negative mutant of PfRad51 (PF3D7_1107400), PfRad51(K143R), when expressed in Plasmodium berghei, abolishes DSB repair as shown by hypersensitivity to DNA-damaging agents. Mice infected with mutant parasites lived significantly longer with markedly reduced parasite burden. In a yeast surrogate model, PfRad51(K143R) completely inhibited DNA repair, gene conversion, and gene targeting. Biochemically, very low levels of mutant protein were sufficient to disrupt wild-type PfRad51 activity, consistent with a dominant negative mechanism. Homologous recombination (HR) was established as the most important DSB repair pathway in Plasmodium.\",\n      \"method\": \"Dominant negative mutagenesis (K143R), transgenic P. berghei line, DNA damage hypersensitivity assay, mouse infection model, yeast surrogate genetic assay, in vitro biochemical disruption assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transgenic parasite, mouse model, yeast genetics, biochemistry), active-site mutagenesis, clear phenotypic readouts\",\n      \"pmids\": [\"25145341\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Based on the crystal structure of the human BRC4-RAD51 complex, sequence fingerprint analysis predicts that the Plasmodium RAD51 orthologue (PF3D7_1107400) retains the interaction interface required for binding BRC repeat motifs of BRCA2, whereas yeast and archaeal/bacterial RAD51 orthologues and human RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, DMC1) do not fulfil the criteria. A BRCA2 homologue containing BRC repeats was identified in two Plasmodium species.\",\n      \"method\": \"Crystal structure of human BRC4-RAD51 complex used to define interaction fingerprints; comparative sequence analysis applied to Plasmodium RAD51\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — interaction prediction is computational/structural inference from the human complex; no direct biochemical validation of Plasmodium RAD51–BRCA2 interaction was performed\",\n      \"pmids\": [\"12967658\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The small molecule B02 docks with high affinity to the predicted tertiary structure of PfRad51 (PF3D7_1107400), blocks its ATPase and strand-exchange activities in vitro, abrogates formation of PfRad51 foci on damaged DNA, and inhibits P. falciparum growth (IC50 8 µM in 3D7, 3 µM in Dd2). B02 synergizes with artemisinin and chloroquine (reducing their IC50 values by 15- and 8-fold, respectively) and causes accumulation of unrepaired parasitic DNA. Disruption of homomeric PfRad51 interactions was proposed as the mechanism, consistent with B02 blocking filament formation.\",\n      \"method\": \"In silico docking, in vitro ATPase assay, in vitro strand exchange assay, immunofluorescence microscopy of PfRad51 foci, parasite growth inhibition assay, drug synergy assay, DNA damage accumulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal in vitro biochemical assays (ATPase, strand exchange) combined with cellular imaging and parasite growth readouts in a single rigorous study; single lab\",\n      \"pmids\": [\"30936202\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In P. falciparum, homologous recombination (HR) and de novo telomere addition compete to repair DSBs in subtelomeric regions, with the pathway used determined by the DNA sequences immediately surrounding the break. Both pathways were observed in response to spontaneous and experimentally induced DSBs, demonstrating that HR (in which PfRad51 participates) is active in repairing DSBs within subtelomeric regions.\",\n      \"method\": \"Single-molecule real-time (SMRT) sequencing of subtelomeric repair products from spontaneous and induced DSBs in P. falciparum culture\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SMRT sequencing provides direct molecular evidence of repair products; HR pathway involvement inferred from product sequences without direct disruption of PfRad51 in this study\",\n      \"pmids\": [\"28790200\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PfRad51 (PF3D7_1107400) interacts with PfExomit2, a mitochondria-localised exonuclease, in pull-down assays, suggesting that PfRad51 is a component of the mitochondrial double-strand break repair (DSBR) pathway in P. falciparum.\",\n      \"method\": \"Pull-down assay with recombinant proteins; immunofluorescence localization of interacting partners\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down assay, single lab, no functional validation of the PfRad51–PfExomit2 interaction beyond physical association\",\n      \"pmids\": [\"41243319\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockout of PfRad51 (PF3D7_1107400) in P. falciparum causes uniform hypersensitivity to irradiation across the erythrocytic cell cycle. PfRad51 is essential for HR-mediated repair of targeted DSBs in the conserved core genome. In contrast, when DSBs are induced in subtelomeric regions, a Rad51-independent, homology-directed repair pathway operates, indicating that PfRad51 is dispensable for subtelomeric DSB repair.\",\n      \"method\": \"Genetic knockout (PfRad51Δ), irradiation hypersensitivity assay across the cell cycle, targeted DSB induction with sequencing of repair products\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined phenotypic readouts (irradiation sensitivity, directed DSB repair outcomes), multiple assays, single lab\",\n      \"pmids\": [\"41277688\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockout of PfRad51 (PF3D7_1107400) in P. falciparum causes uniform irradiation hypersensitivity across the erythrocytic cycle and is essential for HR-mediated repair in the core genome, while a Rad51-independent homology-directed repair pathway operates in subtelomeric regions (preprint version of the peer-reviewed paper).\",\n      \"method\": \"Genetic knockout, irradiation sensitivity assay, targeted DSB repair sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint counterpart of peer-reviewed finding; consistent results, single lab; downgraded from High because preprint status\",\n      \"pmids\": [\"40667286\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfRad51 (PF3D7_1107400) is the Plasmodium falciparum RecA/Rad51 recombinase that exhibits ATPase activity, catalyses ATP-dependent DNA strand exchange in vitro, and is the primary driver of homologous recombination (HR)-mediated repair of double-strand breaks (DSBs) in the parasite core genome; its activity is stimulated by PfRad54 and PfRPA1L, negatively modulated by PfRPA1S, and its dominant-negative K143R mutation or small-molecule inhibition (B02) abolishes DSB repair and reduces parasite survival, while subtelomeric DSBs are repaired by a PfRad51-independent, homology-directed pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1107400 (PfRad51) is the RecA/Rad51-family recombinase that drives homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) in Plasmodium falciparum, and its transcript and protein are induced upon MMS-induced DNA damage [#0, #1]. Biochemically, recombinant PfRad51 hydrolyzes ATP and catalyzes ATP-dependent DNA strand exchange in vitro; this activity is accelerated by PfRad54 and stimulated by the replication protein A homologue PfRPA1L, while PfRPA1S negatively modulates PfRPA1L in a dose-dependent manner [#1]. The catalytic requirement is demonstrated by the K143R active-site mutant, which acts dominant-negatively to abolish DSB repair, gene conversion, and gene targeting, establishing HR as the principal DSB repair pathway in Plasmodium [#2]. Genetic knockout confirms that PfRad51 is essential for HR-mediated repair of DSBs in the conserved core genome and produces uniform irradiation hypersensitivity across the erythrocytic cycle, whereas subtelomeric DSBs are repaired by a PfRad51-independent, homology-directed pathway [#7]. Small-molecule inhibition by B02 blocks PfRad51 ATPase and strand-exchange activities, abrogates damage-induced PfRad51 foci, causes accumulation of unrepaired DNA, and inhibits parasite growth in synergy with artemisinin and chloroquine, consistent with disruption of homomeric filament formation [#4]. Beyond these findings, PfRad51's interaction with the BRCA2 BRC-repeat interface [#3] and with the mitochondrial exonuclease PfExomit2 [#6] have not been experimentally validated beyond structural prediction and a single pull-down, respectively.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether Plasmodium encodes a bona fide Rad51 recombinase and whether it participates in damage responses was unknown; identification of a Rad51 orthologue induced by a DNA-damaging agent placed PF3D7_1107400 in recombinational repair.\",\n      \"evidence\": \"Gene identification, sequence analysis, and RT-PCR/Western blot of MMS-treated P. falciparum cultures\",\n      \"pmids\": [\"14527521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro recombinase activity demonstrated\", \"Direct role in DSB repair not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether PfRad51 could engage a BRCA2-type mediator was addressed computationally, predicting the parasite orthologue retains the BRC-repeat interaction interface unlike other family members.\",\n      \"evidence\": \"Structural fingerprint analysis from the human BRC4-RAD51 crystal structure applied to Plasmodium RAD51 sequence\",\n      \"pmids\": [\"12967658\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational inference; no biochemical validation of a PfRad51-BRCA2 interaction\", \"No demonstration that a Plasmodium BRC repeat binds PfRad51\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The catalytic activity of PfRad51 and its regulation were undefined; in vitro reconstitution established ATPase and strand-exchange activity and identified stimulatory (PfRad54, PfRPA1L) and inhibitory (PfRPA1S) partners.\",\n      \"evidence\": \"In vitro ATPase and strand-exchange assays with recombinant proteins, comet assay, and expression analysis in P. falciparum\",\n      \"pmids\": [\"23631919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner interactions shown biochemically but not validated in vivo\", \"Stoichiometry and filament architecture not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether PfRad51 catalytic function is required for parasite DSB repair and survival was answered by an active-site dominant-negative mutant that abolished repair and reduced parasite burden, establishing HR as the dominant DSB repair route.\",\n      \"evidence\": \"K143R dominant-negative mutagenesis in transgenic P. berghei, mouse infection model, yeast surrogate genetics, and in vitro disruption assay\",\n      \"pmids\": [\"25145341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative rather than clean loss-of-function in P. falciparum\", \"Contribution of specific partners in vivo not dissected\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"How subtelomeric DSBs are repaired was probed by sequencing repair products, showing HR competes with de novo telomere addition and that pathway choice is dictated by local sequence.\",\n      \"evidence\": \"SMRT sequencing of subtelomeric repair products from spontaneous and induced DSBs in P. falciparum\",\n      \"pmids\": [\"28790200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HR involvement inferred from product sequences without direct PfRad51 disruption\", \"Exact PfRad51 dependence at subtelomeres not tested here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether PfRad51 is druggable was tested with B02, which blocked its enzymatic activities and foci formation, killed parasites, and synergized with front-line antimalarials, nominating PfRad51 as a chemotherapeutic target.\",\n      \"evidence\": \"In silico docking, in vitro ATPase and strand-exchange assays, immunofluorescence of PfRad51 foci, growth inhibition and drug synergy assays in P. falciparum 3D7 and Dd2\",\n      \"pmids\": [\"30936202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Filament-disruption mechanism proposed but not structurally confirmed\", \"B02 selectivity for PfRad51 versus host RAD51 not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether PfRad51 is genuinely essential for HR and whether all DSBs depend on it was resolved by knockout, showing it is required for core-genome HR and uniform irradiation resistance but dispensable for a distinct subtelomeric homology-directed pathway.\",\n      \"evidence\": \"PfRad51 genetic knockout, irradiation hypersensitivity across the erythrocytic cycle, and targeted DSB repair-product sequencing in P. falciparum (peer-reviewed; also as bioRxiv preprint)\",\n      \"pmids\": [\"41277688\", \"40667286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the Rad51-independent subtelomeric pathway not defined\", \"Mechanistic basis of pathway partitioning by genomic region unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether PfRad51 acts beyond nuclear HR was raised by a physical interaction with a mitochondrial exonuclease, hinting at a mitochondrial DSB repair role.\",\n      \"evidence\": \"Pull-down assay with recombinant PfExomit2 and immunofluorescence localization in P. falciparum\",\n      \"pmids\": [\"41243319\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pull-down without reciprocal or functional validation\", \"No evidence PfRad51 localizes to or acts within mitochondria\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the PfRad51-independent subtelomeric homology-directed repair machinery, and whether PfRad51 has a bona fide functional role in mitochondrial DSB repair, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Effectors of Rad51-independent subtelomeric repair unidentified\", \"Functional consequence of PfExomit2 interaction untested\", \"In vivo relevance of BRCA2/BRC-repeat prediction unconfirmed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0000150\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0008094\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0000724\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0006302\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0006281\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfRad54 (accelerates PfRad51-mediated homologous pairing) [#1]\",\n      \"PfRPA1L (stimulates PfRad51 strand exchange) [#1]\",\n      \"PfRPA1S (negatively regulates PfRPA1L) [#1]\",\n      \"PfExomit2 (mitochondrial exonuclease; physical pull-down interaction, unvalidated) [#6]\"\n    ],\n    \"other_free_text\": [\n      \"K143R active-site substitution acts as a dominant-negative, abolishing DSB repair, gene conversion, and gene targeting [#2]\",\n      \"Small-molecule inhibitor B02 blocks ATPase and strand-exchange activity, damage-induced foci formation, and parasite growth, synergizing with artemisinin and chloroquine [#4]\",\n      \"Essential for HR repair of core-genome DSBs but dispensable for a Rad51-independent, homology-directed subtelomeric repair pathway [#7]\",\n      \"BRCA2 BRC-repeat interaction interface predicted by structural fingerprint analysis but not experimentally validated [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1107400","name":null,"product":"DNA repair protein RAD51","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0939500","name":null,"product":"DNA repair protein RAD51","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0905000","name":null,"product":"DNA repair protein RAD51, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RAD51","evaluation":null}