{"gene":"PF3D7_1118600","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2010,"finding":"Recombinant PfMYST (MYST/PF3D7_1118600) purified from P. falciparum parasites (but not from prokaryotes or insect cells) exhibited histone acetyltransferase activity with a predilection to acetylate histone H4 in vitro at K5, K8, K12, and K16.","method":"In vitro HAT activity assay using recombinant protein purified from parasites; comparison with prokaryote- and insect-cell-expressed protein","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with substrate-site resolution, single lab with multiple expression systems tested as controls","pmids":["20807207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"PfMYST (MYST/PF3D7_1118600) tagged with GFP at the C-terminus localizes to both the nucleus and the cytoplasm in intraerythrocytic stages, and is expressed as both a long and a short isoform.","method":"GFP tagging and live fluorescence microscopy; Western blot showing two isoforms","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by live imaging with GFP tag, single lab, no functional rescue","pmids":["20807207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"PfMYST (MYST/PF3D7_1118600) is recruited to the active var gene promoter, consistent with its role in H4 acetylation and active gene expression.","method":"Chromatin immunoprecipitation (ChIP) at active var promoter","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP demonstrating promoter occupancy, single lab, single method","pmids":["20807207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Overexpression of either the long (active) or a truncated (non-active) version of PfMYST (MYST/PF3D7_1118600) by stable genomic integration altered global H4 acetylation levels and cell cycle progression, and affected sensitivity to DNA-damaging agents. Attempts to disrupt PfMYST were unsuccessful, indicating it is essential for asexual intraerythrocytic growth.","method":"Stable overexpression by genomic integration; flow cytometry for cell cycle; HAT activity comparison between isoforms; gene disruption attempts","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (overexpression, disruption attempts, cell-cycle analysis), single lab","pmids":["20807207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Using specific transgenic lines and inhibitors, PfMYST (MYST/PF3D7_1118600) and lysine deacetylases were shown to play important roles in regulating the dynamics of cytoplasmic protein acetylation in P. falciparum.","method":"Transgenic parasite lines (PfMYST overexpression) combined with inhibitor treatment; immunoisolation and LC-MS/MS acetylome profiling","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional acetylome readout with transgenic lines and inhibitors, single lab, single study","pmids":["23796209"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"PfRUVBL3 was identified as a physical interacting partner of PfMYST (MYST/PF3D7_1118600) by co-immunoprecipitation; together they colocalize with H3K9me1 histone in the parasitophorous vacuole during the ring stage, suggesting involvement in chromatin remodeling.","method":"Co-immunoprecipitation (pulldown); co-immunofluorescence/colocalization with H3K9me1","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP plus colocalization, single lab, no functional reconstitution","pmids":["30026605"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PfMYST (MYST/PF3D7_1118600) was established as a functional homolog of human TIP60 by yeast complementation assay; NU9056 (an HsTIP60 inhibitor) inhibits PfMYST catalytic activity and kills P. falciparum in culture, arresting parasites at the trophozoite stage and blocking transition to the schizont stage.","method":"Yeast complementation assay; in vitro catalytic activity inhibition with NU9056; parasite growth inhibition assay with stage-specific analysis","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast complementation establishes functional homology, in vitro inhibition of catalytic activity, and cell-biological consequence all in one study, single lab","pmids":["33046499"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfMYST (MYST/PF3D7_1118600) is expressed in two isoforms (long ~72 kDa and short ~45 kDa), with the shorter isoform predominantly nuclear. PfMYST associates with putative autonomously replicating sequences (PfARS) more strongly than PfGCN5, concomitant with enriched H4 acetylation at these sites and correlation with the replication protein PfORC1 and trophozoite stage, indicating a role in DNA replication.","method":"Western blot for isoform characterization; ChIP-qPCR at PfARS for PfMYST, PfGCN5, H4 acetylation, and PfORC1; stage-specific analysis","journal":"Experimental parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple marks and comparison to ORC1 binding, single lab, two orthogonal ChIP readouts","pmids":["36228701"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfMYST (MYST/PF3D7_1118600) and PfRUVBL proteins co-occupy the subtelomeric TARE region and var gene promoters at the ring stage, and the PfMYST/PfRUVBL complex interacts with core histones H3 and H4, implicating this complex in monoallelic var gene regulation.","method":"ChIP at TARE region and var promoters; co-immunoprecipitation demonstrating interaction with H3 and H4","journal":"Pathogens and disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — ChIP occupancy and Co-IP with histones, single lab, limited functional follow-up","pmids":["35640888"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfMYST (MYST/PF3D7_1118600) forms a NuA4-like complex (PfNuA4) containing 11 of 13 conserved NuA4 subunits, identified by reciprocal pulldowns via PfEAF2. Overexpression of PfMYST elevated basal γ-PfH2A (mark of DNA double-strand breaks), conferred protection against MMS, X-rays, and artemisinin, while knockdown caused delayed recovery after MMS treatment. DNA damage triggered cytoplasm-to-nucleus translocation of PfMYST and its colocalization with γ-PfH2A at damage sites.","method":"Reciprocal co-immunoprecipitation/pulldown for complex identification; MS for subunit identification; PfMYST overexpression and knockdown; γ-H2A immunofluorescence; live imaging for subcellular localization upon DNA damage; growth assays with MMS/X-ray/artemisinin","journal":"mSphere","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown confirming complex, multiple orthogonal functional assays (OE, KD, genotoxic agents, live imaging for shuttling), single lab but rigorous multi-method approach","pmids":["38564734"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"Alteration of PfMYST (MYST/PF3D7_1118600) expression via inducible CRISPRi/a (dCas9-GCN5 or dCas9-Sir2a with DiCre/loxP) resulted in altered sensitivity to artemisinin, confirming that PfMYST expression level modulates drug response.","method":"Inducible CRISPRi/a (DiCre/loxP-controlled dCas9-GCN5/-Sir2a); artemisinin sensitivity assay","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional genetic perturbation with defined drug-sensitivity phenotype, single lab, limited mechanistic depth","pmids":["35510853"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Among all putative histone acetyltransferases in P. falciparum, only PfMYST (MYST/PF3D7_1118600) showed a full association with ring-stage survival (RS) phenotype after artemisinin treatment across field isolates; knockdown of PfMYST confirmed linkage of its expression to RS modulation; ChIP-seq and single-cell RNA-seq identified PfMYST-targeted RS-related genes validated by CRISPR/Cas9 manipulation; multi-omics analysis revealed interplay between PfMYST and PfK13 mechanisms.","method":"Systematic evaluation in 30 culture-adapted and 43 subcloned field isolates; knockdown experiments; ChIP-seq; single-cell RNA sequencing; CRISPR/Cas9 genetic manipulation; ring-stage survival assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, scRNA-seq, CRISPR validation, KD) across large sets of field isolates, replication across independent isolates","pmids":["40877256"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1118600 (MYST) is an essential histone acetyltransferase in P. falciparum that acetylates histone H4 at K5, K8, K12, and K16; it exists as long and short isoforms that shuttle between the cytoplasm and nucleus (the short isoform being predominantly nuclear), forms a divergent NuA4-like complex (PfNuA4) and interacts with PfRUVBL proteins, occupies active var gene promoters and autonomously replicating sequences to regulate transcription and DNA replication, is recruited to DNA double-strand break sites (marked by γ-PfH2A) where it promotes repair, and its expression level controls cell cycle progression, antigenic variation, and ring-stage survival after artemisinin treatment."},"narrative":{"mechanistic_narrative":"PF3D7_1118600 (MYST) is an essential histone acetyltransferase that couples chromatin acetylation to transcriptional control, DNA replication, DNA-damage repair, and drug-response phenotypes in the P. falciparum intraerythrocytic cycle [PMID:20807207, PMID:38564734]. Recombinant MYST purified from parasites acetylates histone H4 at K5, K8, K12, and K16 in vitro, and its catalytic activity is required in vivo: gene-disruption attempts fail while overexpression of active versus catalytically inactive isoforms alters global H4 acetylation and cell-cycle progression [PMID:20807207]. MYST is expressed as long (~72 kDa) and short (~45 kDa) isoforms distributed between cytoplasm and nucleus, the short isoform being predominantly nuclear [PMID:20807207, PMID:36228701]. Functional homology to human TIP60 was established by yeast complementation, and the TIP60 inhibitor NU9056 blocks MYST catalytic activity and arrests parasites at the trophozoite-to-schizont transition [PMID:33046499]. Chromatin-level roles include occupancy of active var promoters and the subtelomeric TARE region linked to monoallelic var regulation, and stronger association than PfGCN5 with putative autonomously replicating sequences (PfARS) alongside enriched H4 acetylation and the replication factor PfORC1 [PMID:20807207, PMID:36228701, PMID:35640888]. MYST assembles into a divergent NuA4-like complex (PfNuA4) containing 11 of 13 conserved subunits and interacts with PfRUVBL proteins and core histones H3/H4; upon DNA damage it translocates from cytoplasm to nucleus and colocalizes with γ-PfH2A at double-strand breaks, where its abundance controls repair kinetics and resistance to genotoxic agents and artemisinin [PMID:30026605, PMID:35640888, PMID:38564734]. MYST expression level modulates artemisinin ring-stage survival, and among all P. falciparum HATs only MYST showed full association with the ring-stage survival phenotype across field isolates, with its target genes intersecting PfK13 biology [PMID:35510853, PMID:40877256].","teleology":[{"year":2010,"claim":"Establishing whether PF3D7_1118600 is a bona fide histone acetyltransferase and defining its substrate specificity was the foundational question; the in vitro assay showed it acetylates H4 at specific lysines, defining its molecular activity.","evidence":"In vitro HAT assay with recombinant protein purified from parasites versus prokaryotic/insect-cell systems","pmids":["20807207"],"confidence":"High","gaps":["Why activity requires parasite-derived protein (post-translational modification or bound cofactor) unresolved","No structure of the catalytic domain"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Localization and isoform analysis addressed where the enzyme acts; GFP tagging showed dual nucleo-cytoplasmic distribution and two isoforms, hinting at multiple functional pools.","evidence":"C-terminal GFP tagging with live imaging and Western blot","pmids":["20807207"],"confidence":"Medium","gaps":["Origin and independent function of long versus short isoforms not defined at this stage","No functional rescue of the tag"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Linking the enzyme to gene regulation, ChIP placed MYST at the active var promoter, connecting its H4 acetylation activity to active transcription.","evidence":"ChIP at active var promoter","pmids":["20807207"],"confidence":"Medium","gaps":["Single method, single promoter","Causality between occupancy and var activation not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Genetic essentiality and cellular consequence were tested; disruption failed while active/inactive overexpression altered H4 acetylation, cell cycle, and DNA-damage sensitivity, establishing MYST as essential and functionally coupled to genome maintenance.","evidence":"Stable overexpression, gene-disruption attempts, flow cytometry, isoform HAT comparison","pmids":["20807207"],"confidence":"Medium","gaps":["Essentiality inferred from failed disruption rather than conditional knockout","Direct DNA-repair role not yet demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Whether MYST acts beyond histones was probed; acetylome profiling with transgenic lines and inhibitors implicated it in the dynamics of cytoplasmic protein acetylation.","evidence":"Transgenic overexpression lines plus inhibitors with LC-MS/MS acetylome profiling","pmids":["23796209"],"confidence":"Medium","gaps":["Direct non-histone substrates of MYST not individually validated","Contribution of deacetylases versus MYST not fully separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Identifying protein partners, Co-IP revealed PfRUVBL3 as a physical interactor colocalizing with H3K9me1, pointing to a chromatin-remodeling context.","evidence":"Co-immunoprecipitation and co-immunofluorescence with H3K9me1","pmids":["30026605"],"confidence":"Medium","gaps":["Single Co-IP without functional reconstitution","Functional consequence of the MYST-RUVBL3 interaction untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Cross-species functional identity and druggability were established; yeast complementation defined MYST as a TIP60 homolog and the TIP60 inhibitor NU9056 blocked its activity and arrested parasites, validating it as a target.","evidence":"Yeast complementation, in vitro catalytic inhibition with NU9056, stage-specific growth assays","pmids":["33046499"],"confidence":"High","gaps":["NU9056 selectivity for MYST over other parasite HATs not fully resolved","Molecular basis of trophozoite-stage arrest not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"The link to genome replication was tested; isoform-resolved ChIP showed the nuclear short isoform binds PfARS more strongly than PfGCN5 with enriched H4ac correlating with PfORC1, implicating MYST in DNA replication.","evidence":"Western blot isoform characterization and ChIP-qPCR at PfARS for MYST, GCN5, H4ac and PfORC1","pmids":["36228701"],"confidence":"Medium","gaps":["Direct requirement of MYST for origin firing not demonstrated","Mechanism connecting H4 acetylation to PfORC1 recruitment unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"The role in antigenic variation was extended; ChIP and Co-IP showed MYST and PfRUVBL co-occupy TARE and var promoters and bind core histones H3/H4, implicating the complex in monoallelic var regulation.","evidence":"ChIP at TARE and var promoters and Co-IP with histones H3 and H4","pmids":["35640888"],"confidence":"Medium","gaps":["Causal control of var monoallelic expression not perturbed genetically","Limited functional follow-up"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Whether MYST dosage modulates drug response was addressed; inducible CRISPRi/a tuning of MYST expression altered artemisinin sensitivity, linking its level to drug response.","evidence":"Inducible DiCre/loxP-controlled dCas9-GCN5/-Sir2a CRISPRi/a and artemisinin sensitivity assays","pmids":["35510853"],"confidence":"Medium","gaps":["Downstream mediators of altered sensitivity not identified","Limited mechanistic depth"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"The complex identity and DNA-repair mechanism were resolved; reciprocal pulldowns defined a NuA4-like complex (PfNuA4), and overexpression/knockdown with genotoxic challenge plus damage-induced nuclear translocation to γ-PfH2A foci established MYST as a repair-promoting, dose-dependent protective factor.","evidence":"Reciprocal Co-IP/MS via PfEAF2, overexpression and knockdown, γ-H2A immunofluorescence, live imaging, MMS/X-ray/artemisinin growth assays","pmids":["38564734"],"confidence":"High","gaps":["Signal driving cytoplasm-to-nucleus translocation upon damage unknown","Which repair pathway (HR vs NHEJ) MYST acetylation promotes not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Clinical relevance was established; across field isolates only MYST fully associated with ring-stage survival, and ChIP-seq/scRNA-seq/CRISPR defined its RS-related target genes and intersection with PfK13, positioning MYST in artemisinin resistance biology.","evidence":"Systematic evaluation of 30 culture-adapted and 43 subcloned field isolates, knockdown, ChIP-seq, single-cell RNA-seq, CRISPR/Cas9 validation, ring-stage survival assays","pmids":["40877256"],"confidence":"High","gaps":["Direct molecular interplay between MYST and PfK13 not mechanistically resolved","Whether MYST-driven RS is causal or correlative across all isolates not fully separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How MYST's distinct roles in var regulation, replication-origin function, and DNA-damage repair are coordinated by isoform choice, complex composition, and damage signaling remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of MYST or PfNuA4","Mechanism partitioning long versus short isoforms between functions unknown","Direct causal link between MYST activity and artemisinin resistance mechanism unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfNuA4 (divergent NuA4-like histone acetyltransferase complex, 11 of 13 conserved subunits, identified via PfEAF2) [#9]","PfMYST/PfRUVBL complex [#5, #8]"],"partners":["PFRUVBL3 [#5]","PFRUVBL PROTEINS [#8]","PFEAF2 (NUA4 SUBUNIT USED FOR RECIPROCAL PULLDOWN) [#9]","CORE HISTONES H3 AND H4 [#8]","PFORC1 (CORRELATED CO-OCCUPANCY AT PFARS) [#7]"],"other_free_text":["Acetylates histone H4 at K5, K8, K12, K16 in vitro [#0]","Functional homolog of human TIP60; catalytic activity inhibited by NU9056 [#6]","Essential for asexual intraerythrocytic growth (disruption attempts unsuccessful) [#3]","Expressed as long (~72 kDa) and short (~45 kDa) isoforms; short isoform predominantly nuclear [#1, #7]","Translocates cytoplasm-to-nucleus and colocalizes with γ-PfH2A at DNA double-strand breaks; dose-dependent protection against MMS, X-rays, and artemisinin [#9]","Implicated in cytoplasmic (non-histone) protein acetylation dynamics [#4]","Expression level modulates artemisinin ring-stage survival; only HAT fully associated with RS phenotype across field isolates; targets intersect PfK13 biology [#10, #11]","Occupies active var promoters and subtelomeric TARE region implicated in monoallelic var regulation [#2, #8]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"20453074","id":"PMC_20453074","title":"Chromatin-mediated epigenetic regulation in the malaria parasite Plasmodium falciparum.","date":"2010","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/20453074","citation_count":96,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23796209","id":"PMC_23796209","title":"Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23796209","citation_count":77,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20807207","id":"PMC_20807207","title":"The MYST family histone acetyltransferase regulates gene expression and cell cycle in malaria parasite Plasmodium falciparum.","date":"2010","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20807207","citation_count":63,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MYST","PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35510853","id":"PMC_35510853","title":"A Leak-Free Inducible CRISPRi/a System for Gene Functional Studies in Plasmodium falciparum.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/35510853","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33046499","id":"PMC_33046499","title":"Inhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and Survival.","date":"2020","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/33046499","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30026605","id":"PMC_30026605","title":"Plasmodium falciparum RUVBL3 protein: a novel DNA modifying enzyme and an interacting partner of essential HAT protein MYST.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30026605","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MYST","PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36228701","id":"PMC_36228701","title":"Role of PfMYST in DNA replication in Plasmodium falciparum.","date":"2022","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/36228701","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MYST","PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38564734","id":"PMC_38564734","title":"MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum.","date":"2024","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/38564734","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MYST","PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40877256","id":"PMC_40877256","title":"Epigenetically conferred ring-stage survival in Plasmodium falciparum against artemisinin treatment.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40877256","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35640888","id":"PMC_35640888","title":"Plasmodium falciparum PfRUVBL proteins bind at the TARE region and var gene promoter located in the subtelomeric region.","date":"2022","source":"Pathogens and disease","url":"https://pubmed.ncbi.nlm.nih.gov/35640888","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMYST"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8234,"output_tokens":3509,"usd":0.038669,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9229,"output_tokens":5185,"usd":0.087885,"stage2_stop_reason":"end_turn"},"total_usd":0.126554,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant PfMYST (MYST/PF3D7_1118600) purified from P. falciparum parasites (but not from prokaryotes or insect cells) exhibited histone acetyltransferase activity with a predilection to acetylate histone H4 in vitro at K5, K8, K12, and K16.\",\n      \"method\": \"In vitro HAT activity assay using recombinant protein purified from parasites; comparison with prokaryote- and insect-cell-expressed protein\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with substrate-site resolution, single lab with multiple expression systems tested as controls\",\n      \"pmids\": [\"20807207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) tagged with GFP at the C-terminus localizes to both the nucleus and the cytoplasm in intraerythrocytic stages, and is expressed as both a long and a short isoform.\",\n      \"method\": \"GFP tagging and live fluorescence microscopy; Western blot showing two isoforms\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by live imaging with GFP tag, single lab, no functional rescue\",\n      \"pmids\": [\"20807207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) is recruited to the active var gene promoter, consistent with its role in H4 acetylation and active gene expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) at active var promoter\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP demonstrating promoter occupancy, single lab, single method\",\n      \"pmids\": [\"20807207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of either the long (active) or a truncated (non-active) version of PfMYST (MYST/PF3D7_1118600) by stable genomic integration altered global H4 acetylation levels and cell cycle progression, and affected sensitivity to DNA-damaging agents. Attempts to disrupt PfMYST were unsuccessful, indicating it is essential for asexual intraerythrocytic growth.\",\n      \"method\": \"Stable overexpression by genomic integration; flow cytometry for cell cycle; HAT activity comparison between isoforms; gene disruption attempts\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (overexpression, disruption attempts, cell-cycle analysis), single lab\",\n      \"pmids\": [\"20807207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Using specific transgenic lines and inhibitors, PfMYST (MYST/PF3D7_1118600) and lysine deacetylases were shown to play important roles in regulating the dynamics of cytoplasmic protein acetylation in P. falciparum.\",\n      \"method\": \"Transgenic parasite lines (PfMYST overexpression) combined with inhibitor treatment; immunoisolation and LC-MS/MS acetylome profiling\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional acetylome readout with transgenic lines and inhibitors, single lab, single study\",\n      \"pmids\": [\"23796209\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PfRUVBL3 was identified as a physical interacting partner of PfMYST (MYST/PF3D7_1118600) by co-immunoprecipitation; together they colocalize with H3K9me1 histone in the parasitophorous vacuole during the ring stage, suggesting involvement in chromatin remodeling.\",\n      \"method\": \"Co-immunoprecipitation (pulldown); co-immunofluorescence/colocalization with H3K9me1\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus colocalization, single lab, no functional reconstitution\",\n      \"pmids\": [\"30026605\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) was established as a functional homolog of human TIP60 by yeast complementation assay; NU9056 (an HsTIP60 inhibitor) inhibits PfMYST catalytic activity and kills P. falciparum in culture, arresting parasites at the trophozoite stage and blocking transition to the schizont stage.\",\n      \"method\": \"Yeast complementation assay; in vitro catalytic activity inhibition with NU9056; parasite growth inhibition assay with stage-specific analysis\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast complementation establishes functional homology, in vitro inhibition of catalytic activity, and cell-biological consequence all in one study, single lab\",\n      \"pmids\": [\"33046499\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) is expressed in two isoforms (long ~72 kDa and short ~45 kDa), with the shorter isoform predominantly nuclear. PfMYST associates with putative autonomously replicating sequences (PfARS) more strongly than PfGCN5, concomitant with enriched H4 acetylation at these sites and correlation with the replication protein PfORC1 and trophozoite stage, indicating a role in DNA replication.\",\n      \"method\": \"Western blot for isoform characterization; ChIP-qPCR at PfARS for PfMYST, PfGCN5, H4 acetylation, and PfORC1; stage-specific analysis\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple marks and comparison to ORC1 binding, single lab, two orthogonal ChIP readouts\",\n      \"pmids\": [\"36228701\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) and PfRUVBL proteins co-occupy the subtelomeric TARE region and var gene promoters at the ring stage, and the PfMYST/PfRUVBL complex interacts with core histones H3 and H4, implicating this complex in monoallelic var gene regulation.\",\n      \"method\": \"ChIP at TARE region and var promoters; co-immunoprecipitation demonstrating interaction with H3 and H4\",\n      \"journal\": \"Pathogens and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — ChIP occupancy and Co-IP with histones, single lab, limited functional follow-up\",\n      \"pmids\": [\"35640888\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfMYST (MYST/PF3D7_1118600) forms a NuA4-like complex (PfNuA4) containing 11 of 13 conserved NuA4 subunits, identified by reciprocal pulldowns via PfEAF2. Overexpression of PfMYST elevated basal γ-PfH2A (mark of DNA double-strand breaks), conferred protection against MMS, X-rays, and artemisinin, while knockdown caused delayed recovery after MMS treatment. DNA damage triggered cytoplasm-to-nucleus translocation of PfMYST and its colocalization with γ-PfH2A at damage sites.\",\n      \"method\": \"Reciprocal co-immunoprecipitation/pulldown for complex identification; MS for subunit identification; PfMYST overexpression and knockdown; γ-H2A immunofluorescence; live imaging for subcellular localization upon DNA damage; growth assays with MMS/X-ray/artemisinin\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown confirming complex, multiple orthogonal functional assays (OE, KD, genotoxic agents, live imaging for shuttling), single lab but rigorous multi-method approach\",\n      \"pmids\": [\"38564734\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alteration of PfMYST (MYST/PF3D7_1118600) expression via inducible CRISPRi/a (dCas9-GCN5 or dCas9-Sir2a with DiCre/loxP) resulted in altered sensitivity to artemisinin, confirming that PfMYST expression level modulates drug response.\",\n      \"method\": \"Inducible CRISPRi/a (DiCre/loxP-controlled dCas9-GCN5/-Sir2a); artemisinin sensitivity assay\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional genetic perturbation with defined drug-sensitivity phenotype, single lab, limited mechanistic depth\",\n      \"pmids\": [\"35510853\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Among all putative histone acetyltransferases in P. falciparum, only PfMYST (MYST/PF3D7_1118600) showed a full association with ring-stage survival (RS) phenotype after artemisinin treatment across field isolates; knockdown of PfMYST confirmed linkage of its expression to RS modulation; ChIP-seq and single-cell RNA-seq identified PfMYST-targeted RS-related genes validated by CRISPR/Cas9 manipulation; multi-omics analysis revealed interplay between PfMYST and PfK13 mechanisms.\",\n      \"method\": \"Systematic evaluation in 30 culture-adapted and 43 subcloned field isolates; knockdown experiments; ChIP-seq; single-cell RNA sequencing; CRISPR/Cas9 genetic manipulation; ring-stage survival assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, scRNA-seq, CRISPR validation, KD) across large sets of field isolates, replication across independent isolates\",\n      \"pmids\": [\"40877256\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1118600 (MYST) is an essential histone acetyltransferase in P. falciparum that acetylates histone H4 at K5, K8, K12, and K16; it exists as long and short isoforms that shuttle between the cytoplasm and nucleus (the short isoform being predominantly nuclear), forms a divergent NuA4-like complex (PfNuA4) and interacts with PfRUVBL proteins, occupies active var gene promoters and autonomously replicating sequences to regulate transcription and DNA replication, is recruited to DNA double-strand break sites (marked by γ-PfH2A) where it promotes repair, and its expression level controls cell cycle progression, antigenic variation, and ring-stage survival after artemisinin treatment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1118600 (MYST) is an essential histone acetyltransferase that couples chromatin acetylation to transcriptional control, DNA replication, DNA-damage repair, and drug-response phenotypes in the P. falciparum intraerythrocytic cycle [#0, #3, #9]. Recombinant MYST purified from parasites acetylates histone H4 at K5, K8, K12, and K16 in vitro, and its catalytic activity is required in vivo: gene-disruption attempts fail while overexpression of active versus catalytically inactive isoforms alters global H4 acetylation and cell-cycle progression [#0, #3]. MYST is expressed as long (~72 kDa) and short (~45 kDa) isoforms distributed between cytoplasm and nucleus, the short isoform being predominantly nuclear [#1, #7]. Functional homology to human TIP60 was established by yeast complementation, and the TIP60 inhibitor NU9056 blocks MYST catalytic activity and arrests parasites at the trophozoite-to-schizont transition [#6]. Chromatin-level roles include occupancy of active var promoters and the subtelomeric TARE region linked to monoallelic var regulation, and stronger association than PfGCN5 with putative autonomously replicating sequences (PfARS) alongside enriched H4 acetylation and the replication factor PfORC1 [#2, #7, #8]. MYST assembles into a divergent NuA4-like complex (PfNuA4) containing 11 of 13 conserved subunits and interacts with PfRUVBL proteins and core histones H3/H4; upon DNA damage it translocates from cytoplasm to nucleus and colocalizes with \\u03b3-PfH2A at double-strand breaks, where its abundance controls repair kinetics and resistance to genotoxic agents and artemisinin [#5, #8, #9]. MYST expression level modulates artemisinin ring-stage survival, and among all P. falciparum HATs only MYST showed full association with the ring-stage survival phenotype across field isolates, with its target genes intersecting PfK13 biology [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing whether PF3D7_1118600 is a bona fide histone acetyltransferase and defining its substrate specificity was the foundational question; the in vitro assay showed it acetylates H4 at specific lysines, defining its molecular activity.\",\n      \"evidence\": \"In vitro HAT assay with recombinant protein purified from parasites versus prokaryotic/insect-cell systems\",\n      \"pmids\": [\"20807207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why activity requires parasite-derived protein (post-translational modification or bound cofactor) unresolved\", \"No structure of the catalytic domain\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localization and isoform analysis addressed where the enzyme acts; GFP tagging showed dual nucleo-cytoplasmic distribution and two isoforms, hinting at multiple functional pools.\",\n      \"evidence\": \"C-terminal GFP tagging with live imaging and Western blot\",\n      \"pmids\": [\"20807207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Origin and independent function of long versus short isoforms not defined at this stage\", \"No functional rescue of the tag\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking the enzyme to gene regulation, ChIP placed MYST at the active var promoter, connecting its H4 acetylation activity to active transcription.\",\n      \"evidence\": \"ChIP at active var promoter\",\n      \"pmids\": [\"20807207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single promoter\", \"Causality between occupancy and var activation not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic essentiality and cellular consequence were tested; disruption failed while active/inactive overexpression altered H4 acetylation, cell cycle, and DNA-damage sensitivity, establishing MYST as essential and functionally coupled to genome maintenance.\",\n      \"evidence\": \"Stable overexpression, gene-disruption attempts, flow cytometry, isoform HAT comparison\",\n      \"pmids\": [\"20807207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Essentiality inferred from failed disruption rather than conditional knockout\", \"Direct DNA-repair role not yet demonstrated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether MYST acts beyond histones was probed; acetylome profiling with transgenic lines and inhibitors implicated it in the dynamics of cytoplasmic protein acetylation.\",\n      \"evidence\": \"Transgenic overexpression lines plus inhibitors with LC-MS/MS acetylome profiling\",\n      \"pmids\": [\"23796209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct non-histone substrates of MYST not individually validated\", \"Contribution of deacetylases versus MYST not fully separated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying protein partners, Co-IP revealed PfRUVBL3 as a physical interactor colocalizing with H3K9me1, pointing to a chromatin-remodeling context.\",\n      \"evidence\": \"Co-immunoprecipitation and co-immunofluorescence with H3K9me1\",\n      \"pmids\": [\"30026605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without functional reconstitution\", \"Functional consequence of the MYST-RUVBL3 interaction untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cross-species functional identity and druggability were established; yeast complementation defined MYST as a TIP60 homolog and the TIP60 inhibitor NU9056 blocked its activity and arrested parasites, validating it as a target.\",\n      \"evidence\": \"Yeast complementation, in vitro catalytic inhibition with NU9056, stage-specific growth assays\",\n      \"pmids\": [\"33046499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NU9056 selectivity for MYST over other parasite HATs not fully resolved\", \"Molecular basis of trophozoite-stage arrest not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The link to genome replication was tested; isoform-resolved ChIP showed the nuclear short isoform binds PfARS more strongly than PfGCN5 with enriched H4ac correlating with PfORC1, implicating MYST in DNA replication.\",\n      \"evidence\": \"Western blot isoform characterization and ChIP-qPCR at PfARS for MYST, GCN5, H4ac and PfORC1\",\n      \"pmids\": [\"36228701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct requirement of MYST for origin firing not demonstrated\", \"Mechanism connecting H4 acetylation to PfORC1 recruitment unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The role in antigenic variation was extended; ChIP and Co-IP showed MYST and PfRUVBL co-occupy TARE and var promoters and bind core histones H3/H4, implicating the complex in monoallelic var regulation.\",\n      \"evidence\": \"ChIP at TARE and var promoters and Co-IP with histones H3 and H4\",\n      \"pmids\": [\"35640888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal control of var monoallelic expression not perturbed genetically\", \"Limited functional follow-up\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether MYST dosage modulates drug response was addressed; inducible CRISPRi/a tuning of MYST expression altered artemisinin sensitivity, linking its level to drug response.\",\n      \"evidence\": \"Inducible DiCre/loxP-controlled dCas9-GCN5/-Sir2a CRISPRi/a and artemisinin sensitivity assays\",\n      \"pmids\": [\"35510853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream mediators of altered sensitivity not identified\", \"Limited mechanistic depth\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The complex identity and DNA-repair mechanism were resolved; reciprocal pulldowns defined a NuA4-like complex (PfNuA4), and overexpression/knockdown with genotoxic challenge plus damage-induced nuclear translocation to \\u03b3-PfH2A foci established MYST as a repair-promoting, dose-dependent protective factor.\",\n      \"evidence\": \"Reciprocal Co-IP/MS via PfEAF2, overexpression and knockdown, \\u03b3-H2A immunofluorescence, live imaging, MMS/X-ray/artemisinin growth assays\",\n      \"pmids\": [\"38564734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal driving cytoplasm-to-nucleus translocation upon damage unknown\", \"Which repair pathway (HR vs NHEJ) MYST acetylation promotes not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clinical relevance was established; across field isolates only MYST fully associated with ring-stage survival, and ChIP-seq/scRNA-seq/CRISPR defined its RS-related target genes and intersection with PfK13, positioning MYST in artemisinin resistance biology.\",\n      \"evidence\": \"Systematic evaluation of 30 culture-adapted and 43 subcloned field isolates, knockdown, ChIP-seq, single-cell RNA-seq, CRISPR/Cas9 validation, ring-stage survival assays\",\n      \"pmids\": [\"40877256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular interplay between MYST and PfK13 not mechanistically resolved\", \"Whether MYST-driven RS is causal or correlative across all isolates not fully separated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYST's distinct roles in var regulation, replication-origin function, and DNA-damage repair are coordinated by isoform choice, complex composition, and damage signaling remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of MYST or PfNuA4\", \"Mechanism partitioning long versus short isoforms between functions unknown\", \"Direct causal link between MYST activity and artemisinin resistance mechanism unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004402\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0043998\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 9]},\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0000785\", \"supporting_discovery_ids\": [2, 7, 8]},\n      {\"term_id\": \"GO:0035869\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016573\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0006281\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0006260\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0045893\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0007049\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"PfNuA4 (divergent NuA4-like histone acetyltransferase complex, 11 of 13 conserved subunits, identified via PfEAF2) [#9]\",\n      \"PfMYST/PfRUVBL complex [#5, #8]\"\n    ],\n    \"partners\": [\n      \"PfRUVBL3 [#5]\",\n      \"PfRUVBL proteins [#8]\",\n      \"PfEAF2 (NuA4 subunit used for reciprocal pulldown) [#9]\",\n      \"Core histones H3 and H4 [#8]\",\n      \"PfORC1 (correlated co-occupancy at PfARS) [#7]\"\n    ],\n    \"other_free_text\": [\n      \"Acetylates histone H4 at K5, K8, K12, K16 in vitro [#0]\",\n      \"Functional homolog of human TIP60; catalytic activity inhibited by NU9056 [#6]\",\n      \"Essential for asexual intraerythrocytic growth (disruption attempts unsuccessful) [#3]\",\n      \"Expressed as long (~72 kDa) and short (~45 kDa) isoforms; short isoform predominantly nuclear [#1, #7]\",\n      \"Translocates cytoplasm-to-nucleus and colocalizes with \\u03b3-PfH2A at DNA double-strand breaks; dose-dependent protection against MMS, X-rays, and artemisinin [#9]\",\n      \"Implicated in cytoplasmic (non-histone) protein acetylation dynamics [#4]\",\n      \"Expression level modulates artemisinin ring-stage survival; only HAT fully associated with RS phenotype across field isolates; targets intersect PfK13 biology [#10, #11]\",\n      \"Occupies active var promoters and subtelomeric TARE region implicated in monoallelic var regulation [#2, #8]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1118600","name":null,"product":"histone acetyltransferase MYST","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0929500","name":null,"product":"histone acetyltransferase MYST, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0916300","name":null,"product":"histone acetyltransferase MYST, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"MYST","evaluation":null}