{"gene":"PF3D7_0414000","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2023,"finding":"SMC3 (PF3D7_0414000) knockdown during early stages of the intraerythrocytic developmental cycle (IDC) upregulates a subset of genes involved in erythrocyte egress and invasion that are normally expressed at later stages. ChIP-seq analyses showed that SMC3 enrichment at promoter regions of these genes inversely correlates with gene expression and chromatin accessibility, indicating that SMC3 binding contributes to transcriptional repression of stage-specific genes until their appropriate time of expression.","method":"Inducible knockdown of SMC3 followed by transcriptome analysis; ChIP-seq to map SMC3 occupancy at promoters correlated with chromatin accessibility (ATAC-seq or equivalent)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined transcriptional phenotype plus ChIP-seq mechanistic mapping, single lab but two orthogonal methods","pmids":["37592911"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"SMC3 (ortholog PBANKA_0716000) physically associates with SMC1 (PBANKA_0917500) as part of the cohesin complex. Affinity purification-MS also identified an uncharacterized protein (PBANKA_1304000) containing a Rad21/Rec8-like N-terminal domain as a further SMC3-associated cohesin subunit.","method":"Affinity purification followed by quantitative mass spectrometry (BN-PAGE-AP-MS) in Plasmodium berghei schizonts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-purification/MS experiment validated with AP-MS, single lab, identification of complex partners","pmids":["31390575"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"SMC3 (PF3D7_0414000) was co-precipitated with the male-gametocyte-specific kinase SRPK1 and with MAP2 by immunoprecipitation, placing SMC3 (as part of the cohesin complex with SMC1) in proximity to kinases that regulate rapid DNA replication during endomitosis in male gametogenesis.","method":"Immunoprecipitation of GFP-tagged SRPK1 and MAP2 followed by mass spectrometry in Plasmodium falciparum male gametocytes","journal":"Life science alliance","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/MS experiment, single lab, no direct functional follow-up for SMC3 itself","pmids":["40127922"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"In P. falciparum, SMC3 (PF3D7_0414000) is a subunit of the cohesin complex (physically associating with SMC1 and a Rad21/Rec8-domain protein) that occupies promoter regions of invasion/egress genes during early intraerythrocytic development, where its binding inversely correlates with gene expression and chromatin accessibility and contributes to transcriptional repression of these genes until their appropriate developmental stage."},"narrative":{"mechanistic_narrative":"SMC3 (PF3D7_0414000) is a cohesin subunit in Plasmodium that couples chromosome organization to the developmental timing of gene expression during the intraerythrocytic cycle [PMID:37592911, PMID:31390575]. In P. falciparum, SMC3 occupies the promoter regions of a subset of erythrocyte egress and invasion genes during early intraerythrocytic development, where its enrichment inversely correlates with transcript level and chromatin accessibility; inducible SMC3 knockdown prematurely upregulates these normally later-expressed genes, establishing SMC3 binding as a contributor to stage-specific transcriptional repression [PMID:37592911]. Consistent with a canonical cohesin role, in P. berghei SMC3 physically associates with SMC1 and with an uncharacterized Rad21/Rec8-domain protein as part of the cohesin complex [PMID:31390575]. Beyond these findings, no independent enzymatic activity or structural mechanism has been characterized for SMC3 in the available corpus.","teleology":[{"year":2019,"claim":"Whether Plasmodium SMC3 assembles into a bona fide cohesin complex was unresolved; identifying its physical partners established its complex membership.","evidence":"Affinity purification and quantitative mass spectrometry (BN-PAGE-AP-MS) in P. berghei schizonts","pmids":["31390575"],"confidence":"Medium","gaps":["The Rad21/Rec8-domain partner (PBANKA_1304000) remains uncharacterized functionally","Complex composition shown in P. berghei, not directly demonstrated for the P. falciparum ortholog","Single co-purification without reciprocal or structural validation"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2023,"claim":"It was unknown whether cohesin/SMC3 has a transcriptional role in parasite development; loss-of-function plus occupancy mapping established SMC3 as a repressor timing egress/invasion gene expression.","evidence":"Inducible SMC3 knockdown with transcriptome profiling and ChIP-seq occupancy correlated with chromatin accessibility in P. falciparum","pmids":["37592911"],"confidence":"High","gaps":["Mechanism by which SMC3 occupancy enforces repression (e.g. loop extrusion vs. direct promoter blockade) not resolved","Whether the repressive effect requires the full cohesin complex or SMC3 alone is not distinguished","How SMC3 is recruited to specific promoters is not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether SMC3/cohesin operates during male gametogenesis was open; co-precipitation placed SMC3 near replication-regulating kinases in male gametocytes.","evidence":"Immunoprecipitation of GFP-tagged SRPK1 and MAP2 followed by mass spectrometry in P. falciparum male gametocytes","pmids":["40127922"],"confidence":"Low","gaps":["Single co-IP/MS without reciprocal validation or functional follow-up for SMC3 itself","Direct role of SMC3 in endomitotic DNA replication not tested","Association may be indirect through other cohesin subunits"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How SMC3 is targeted to specific promoters and whether its cohesin biochemical activity (e.g. DNA engagement or loop extrusion) underlies the observed transcriptional repression remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or enzymatic characterization of Plasmodium SMC3","Recruitment determinants at repressed promoters undefined","Functional role in gametocyte-stage replication untested"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["cohesin complex (with SMC1 and a Rad21/Rec8-domain subunit)"],"partners":["SMC1 (PBANKA_0917500)","RAD21/REC8-DOMAIN PROTEIN (PBANKA_1304000)","SRPK1","MAP2"],"other_free_text":["SMC3 enrichment at egress/invasion gene promoters inversely correlates with expression and chromatin accessibility [#0]","Inducible knockdown of SMC3 prematurely upregulates stage-specific egress/invasion genes [#0]","Complex membership demonstrated in P. berghei ortholog; transcriptional repression demonstrated in P. falciparum [#0, #1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"37592911","id":"PMC_37592911","title":"Cohesin contributes to transcriptional repression of stage-specific genes in the human malaria parasite.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37592911","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3","structural maintenance of chromosomes protein 3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39915671","id":"","title":"PfFBXO1 is essential for inner membrane complex formation in Plasmodium falciparum during both asexual and transmission stages.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39915671","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40127922","id":"","title":"Divergent Plasmodium kinases drive MTOC, kinetochore and axoneme organisation in male gametogenesis.","date":"2025","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/40127922","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31390575","id":"","title":"Landscape of the Plasmodium Interactome Reveals Both Conserved and Species-Specific Functionality.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31390575","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32049018","id":"","title":"Plasmodium Condensin Core Subunits SMC2/SMC4 Mediate Atypical Mitosis and Are Essential for Parasite Proliferation and Transmission.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32049018","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38393970","id":"","title":"Noncanonical usage of stop codons in ciliates expands proteins with structurally flexible Q-rich motifs.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38393970","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38498704","id":"","title":"Cip1, a CDK regulator, determines heterothallic mating or homothallic selfing in a protist.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38498704","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25529755","id":"","title":"Sexual reproduction and genetic exchange in parasitic protists.","date":"2014","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25529755","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SMC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10334,"output_tokens":968,"usd":0.022761,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5733,"output_tokens":1909,"usd":0.038195,"stage2_stop_reason":"end_turn"},"total_usd":0.060956,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"SMC3 (PF3D7_0414000) knockdown during early stages of the intraerythrocytic developmental cycle (IDC) upregulates a subset of genes involved in erythrocyte egress and invasion that are normally expressed at later stages. ChIP-seq analyses showed that SMC3 enrichment at promoter regions of these genes inversely correlates with gene expression and chromatin accessibility, indicating that SMC3 binding contributes to transcriptional repression of stage-specific genes until their appropriate time of expression.\",\n      \"method\": \"Inducible knockdown of SMC3 followed by transcriptome analysis; ChIP-seq to map SMC3 occupancy at promoters correlated with chromatin accessibility (ATAC-seq or equivalent)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined transcriptional phenotype plus ChIP-seq mechanistic mapping, single lab but two orthogonal methods\",\n      \"pmids\": [\"37592911\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SMC3 (ortholog PBANKA_0716000) physically associates with SMC1 (PBANKA_0917500) as part of the cohesin complex. Affinity purification-MS also identified an uncharacterized protein (PBANKA_1304000) containing a Rad21/Rec8-like N-terminal domain as a further SMC3-associated cohesin subunit.\",\n      \"method\": \"Affinity purification followed by quantitative mass spectrometry (BN-PAGE-AP-MS) in Plasmodium berghei schizonts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-purification/MS experiment validated with AP-MS, single lab, identification of complex partners\",\n      \"pmids\": [\"31390575\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMC3 (PF3D7_0414000) was co-precipitated with the male-gametocyte-specific kinase SRPK1 and with MAP2 by immunoprecipitation, placing SMC3 (as part of the cohesin complex with SMC1) in proximity to kinases that regulate rapid DNA replication during endomitosis in male gametogenesis.\",\n      \"method\": \"Immunoprecipitation of GFP-tagged SRPK1 and MAP2 followed by mass spectrometry in Plasmodium falciparum male gametocytes\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/MS experiment, single lab, no direct functional follow-up for SMC3 itself\",\n      \"pmids\": [\"40127922\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"In P. falciparum, SMC3 (PF3D7_0414000) is a subunit of the cohesin complex (physically associating with SMC1 and a Rad21/Rec8-domain protein) that occupies promoter regions of invasion/egress genes during early intraerythrocytic development, where its binding inversely correlates with gene expression and chromatin accessibility and contributes to transcriptional repression of these genes until their appropriate developmental stage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMC3 (PF3D7_0414000) is a cohesin subunit in Plasmodium that couples chromosome organization to the developmental timing of gene expression during the intraerythrocytic cycle [#0, #1]. In P. falciparum, SMC3 occupies the promoter regions of a subset of erythrocyte egress and invasion genes during early intraerythrocytic development, where its enrichment inversely correlates with transcript level and chromatin accessibility; inducible SMC3 knockdown prematurely upregulates these normally later-expressed genes, establishing SMC3 binding as a contributor to stage-specific transcriptional repression [#0]. Consistent with a canonical cohesin role, in P. berghei SMC3 physically associates with SMC1 and with an uncharacterized Rad21/Rec8-domain protein as part of the cohesin complex [#1]. Beyond these findings, no independent enzymatic activity or structural mechanism has been characterized for SMC3 in the available corpus.\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether Plasmodium SMC3 assembles into a bona fide cohesin complex was unresolved; identifying its physical partners established its complex membership.\",\n      \"evidence\": \"Affinity purification and quantitative mass spectrometry (BN-PAGE-AP-MS) in P. berghei schizonts\",\n      \"pmids\": [\"31390575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The Rad21/Rec8-domain partner (PBANKA_1304000) remains uncharacterized functionally\",\n        \"Complex composition shown in P. berghei, not directly demonstrated for the P. falciparum ortholog\",\n        \"Single co-purification without reciprocal or structural validation\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"It was unknown whether cohesin/SMC3 has a transcriptional role in parasite development; loss-of-function plus occupancy mapping established SMC3 as a repressor timing egress/invasion gene expression.\",\n      \"evidence\": \"Inducible SMC3 knockdown with transcriptome profiling and ChIP-seq occupancy correlated with chromatin accessibility in P. falciparum\",\n      \"pmids\": [\"37592911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SMC3 occupancy enforces repression (e.g. loop extrusion vs. direct promoter blockade) not resolved\",\n        \"Whether the repressive effect requires the full cohesin complex or SMC3 alone is not distinguished\",\n        \"How SMC3 is recruited to specific promoters is not defined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether SMC3/cohesin operates during male gametogenesis was open; co-precipitation placed SMC3 near replication-regulating kinases in male gametocytes.\",\n      \"evidence\": \"Immunoprecipitation of GFP-tagged SRPK1 and MAP2 followed by mass spectrometry in P. falciparum male gametocytes\",\n      \"pmids\": [\"40127922\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single co-IP/MS without reciprocal validation or functional follow-up for SMC3 itself\",\n        \"Direct role of SMC3 in endomitotic DNA replication not tested\",\n        \"Association may be indirect through other cohesin subunits\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMC3 is targeted to specific promoters and whether its cohesin biochemical activity (e.g. DNA engagement or loop extrusion) underlies the observed transcriptional repression remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or enzymatic characterization of Plasmodium SMC3\",\n        \"Recruitment determinants at repressed promoters undefined\",\n        \"Functional role in gametocyte-stage replication untested\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0045892\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"cohesin complex (with SMC1 and a Rad21/Rec8-domain subunit)\"\n    ],\n    \"partners\": [\n      \"SMC1 (PBANKA_0917500)\",\n      \"Rad21/Rec8-domain protein (PBANKA_1304000)\",\n      \"SRPK1\",\n      \"MAP2\"\n    ],\n    \"other_free_text\": [\n      \"SMC3 enrichment at egress/invasion gene promoters inversely correlates with expression and chromatin accessibility [#0]\",\n      \"Inducible knockdown of SMC3 prematurely upregulates stage-specific egress/invasion genes [#0]\",\n      \"Complex membership demonstrated in P. berghei ortholog; transcriptional repression demonstrated in P. falciparum [#0, #1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0414000","name":null,"product":"structural maintenance of chromosomes protein 3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0716000","name":null,"product":"structural maintenance of chromosomes protein 3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0505600","name":null,"product":"structural maintenance of chromosomes protein 3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SMC3","evaluation":null}