{"gene":"THAP11","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"THAP11 (Ronin) directly binds to HCF-1 (host cell factor 1), a key transcriptional regulator, and this interaction is essential for ES cell self-renewal and pluripotency; conditional knockout of Ronin prevents ES cell growth while forced expression allows proliferation without differentiation.","method":"Conditional knockout mouse model, forced overexpression in ES cells, co-immunoprecipitation/direct binding assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, loss-of-function and gain-of-function experiments with defined cellular phenotypes, replicated in subsequent studies","pmids":["18585351"],"is_preprint":false},{"year":2010,"finding":"The Ronin/HCF-1 complex binds to a hyperconserved enhancer element (ACTACA-containing motif) at promoters of genes involved in transcription initiation, mRNA splicing, and cell metabolism; Ronin/HCF-1 can both repress and activate target genes, with activation of protein biosynthesis and energy production genes predominating.","method":"ChIP-seq, genome-wide binding analysis, gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with expression profiling, builds on prior Co-IP, replicated by subsequent studies","pmids":["20581084"],"is_preprint":false},{"year":2012,"finding":"THAP11 physically associates with HCF-1 and recruits it to target promoters in human colon cancer cells; THAP11-mediated gene regulation and chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11, indicating mutual dependency.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal dependency shown by ChIP + Co-IP + knockdown, single lab but multiple orthogonal methods","pmids":["22371484"],"is_preprint":false},{"year":2012,"finding":"THAP11 interacts with PCBP1 (poly(rC)-binding protein 1), and this interaction is required for THAP11 to inhibit CD44 v6 alternative splicing and cell invasion in hepatoma cells; deletion of the PCBP1-binding domain abolishes this regulatory activity.","method":"Co-immunoprecipitation, pulldown, overexpression/deletion mutants, CD44 splicing assays, invasion assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner identified by Co-IP, domain deletion confirms requirement, single lab","pmids":["22673507"],"is_preprint":false},{"year":2013,"finding":"In human HeLa cells, HCFC1 co-localizes with THAP11 (Ronin) and ZNF143 at ~90% of ~5400 active CpG-island promoters, with the THAP11/ZNF143 binding motif underlying a large fraction of HCFC1 recruitment sites.","method":"ChIP-seq, motif analysis, co-localization analysis","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq across multiple factors, independently replicated direction consistent with other labs","pmids":["23539139"],"is_preprint":false},{"year":2014,"finding":"THAP11, ZNF143, and HCF-1 form a mutually dependent trimeric complex on chromatin at E2F-bound and cell-cycle-control gene promoters; HCF-1 recruitment to these promoters is mediated by THAP11 and ZNF143 rather than E2F proteins directly; disruption of this complex reduces cell proliferation, cell-cycle progression, and cell viability.","method":"ChIP, Co-immunoprecipitation, siRNA knockdown, cell proliferation and cell-cycle assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, loss-of-function with multiple phenotypic readouts, single lab but orthogonal methods","pmids":["25437553"],"is_preprint":false},{"year":2008,"finding":"THAP11 represses transcription of c-Myc in a DNA binding-dependent manner; THAP11 directly binds the c-Myc promoter as shown by ChIP and EMSA; c-Myc overexpression rescues cells from THAP11-mediated growth suppression, establishing c-Myc as a key downstream effector.","method":"Promoter reporter assays, ChIP, EMSA, siRNA knockdown, c-Myc rescue overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro DNA-binding (EMSA), ChIP, promoter reporter, and epistatic rescue experiment, single lab with multiple orthogonal methods","pmids":["19008924"],"is_preprint":false},{"year":2015,"finding":"The ACTACA submotif shared by THAP11 and ZNF143 directs recruitment of THAP11 and HCFC1 to ZNF143-occupied loci; the position, spacing, and orientation of this motif relative to the ZNF143 core motif are critical; CRISPR-Cas9 mutation of the ACTACA submotif at endogenous promoters altered THAP11, ZNF143, and HCFC1 occupancy, gene transcription, and histone modifications.","method":"CRISPR-Cas9 endogenous promoter editing, synthetic chromosomally integrated constructs, ChIP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — CRISPR-Cas9 functional genomics with direct chromatin readout, multiple constructs tested, single lab","pmids":["26416877"],"is_preprint":false},{"year":2016,"finding":"The C-terminal region of human THAP11 forms a left-handed parallel homo-dimeric coiled-coil structure, as determined by X-ray crystallography, with stability and dynamics validated by molecular dynamics simulations and biophysical experiments.","method":"X-ray crystallography, molecular dynamics simulation, biophysical experiments (oligomeric state characterization)","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved with biophysical validation, single lab but Tier 1 method","pmids":["26975212"],"is_preprint":false},{"year":2016,"finding":"RONIN (THAP11) is required for retinal progenitor cell (RPC) proliferation by transcriptionally activating mitochondrial genes including components of electron transport chain complexes I, III, and IV; RPC-specific Ronin loss results in deficient ETC activity, reduced ATP levels, and increased oxidative stress, followed by premature cell-cycle exit.","method":"Conditional knockout mouse model, ChIP, gene expression profiling, ETC activity assays, ATP measurements, ROS measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular and metabolic phenotypes, ChIP linking RONIN to target genes, single lab with multiple orthogonal readouts","pmids":["26876175"],"is_preprint":false},{"year":2017,"finding":"THAP11 and HCFC1 jointly regulate MMACHC expression, and mutations in THAP11 (p.Phe80Leu) result in reduced MMACHC expression causing cobalamin metabolic defects; THAP11 and HCFC1 regulate proliferation and differentiation of neural precursors in zebrafish, with THAP11 loss causing craniofacial abnormalities.","method":"Sanger sequencing, zebrafish morpholino knockdown, RNA-seq, functional assays in developing embryos","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vertebrate model with defined phenotype and overlapping target gene analysis, single lab","pmids":["28449119"],"is_preprint":false},{"year":2017,"finding":"Conditional Ronin knockout sensitizes embryonic stem cells to UV-C-induced DNA damage with ATR pathway activation and G2/M arrest; Ronin binds to and transcriptionally regulates DNA repair factor genes including Gtf2h4 and Rad18.","method":"Conditional knockout ESCs, UV-C treatment, pathway activation assays (ATR), ChIP, gene expression analysis","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined pathway (ATR) activation and ChIP evidence for target genes, single lab, single study","pmids":["28715716"],"is_preprint":false},{"year":2021,"finding":"RONIN (THAP11) and HCF-1 jointly regulate ribosomal protein subunit genes; mouse models with mutations in Hcfc1 and Ronin show reduced ribosomal protein gene expression, ribosome biogenesis defects, translational perturbations, and metabolic defects in addition to loss of Mmachc.","method":"Mouse genetic models, RNA-seq, ribosome biogenesis assays, metabolic analyses","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with multiple molecular phenotypes, two regulators genetically linked to same pathway, single lab","pmids":["35013307"],"is_preprint":false},{"year":2021,"finding":"Ronin is required for active energy production in the embryonic lineage; loss of Ronin results in a reversible quiescent state with promoted naïve pluripotency; Ronin fine-tunes expression of ribosomal protein-encoding genes and is required for tissue-scale organisation of the pluripotent lineage during blastocyst-to-egg-cylinder transition.","method":"Conditional knockout mouse model, metabolic assays, gene expression profiling, embryo morphology","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with metabolic and transcriptional readouts, single lab","pmids":["34515391"],"is_preprint":false},{"year":2021,"finding":"Transgenic overexpression of Ronin in cerebellar Purkinje cells causes Purkinje cell loss and severe ataxia; several SCA-causing genes harbor Ronin DNA-binding motifs and are transcriptionally deregulated in transgenic animals; ectopic Ronin expression increases Ataxin-1 protein levels in ES cells.","method":"Transgenic mouse model, ChIP-based motif analysis, gene expression profiling, Western blot","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transgenic gain-of-function in vivo with motif-based target gene analysis, single lab","pmids":["34165550"],"is_preprint":false},{"year":2023,"finding":"CAG repeat expansion (45–100 repeats) in THAP11 causes SCA51; expanded THAP11 polyQ protein forms intracellular aggregates, redistributes to the cytoplasm in patient fibroblasts and transfected Neuro-2a cells, and shows length-dependent toxicity correlating with pure CAG repeat number.","method":"Long-read whole-genome sequencing, linkage analysis, cell imaging (confocal), transfection of expanded constructs in Neuro-2a cells","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic evidence plus cellular model with aggregation and localization data, replicated in two pedigrees","pmids":["37148549"],"is_preprint":false},{"year":2025,"finding":"Mutant THAP11 with polyQ expansion causes gain-of-function cerebellar neurodegeneration in mice via protein aggregation; mutant THAP11 transcriptionally upregulates TREM2, activating microglia; loss of TREM2 or microglial depletion mitigates neurodegeneration in SCA51 knockin mice.","method":"SCA51 knockin mouse model, viral vector expression in mouse/monkey brains, TREM2 knockout/depletion, gene expression analysis, histology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockin mouse model with genetic epistasis (TREM2 KO rescues phenotype), multiple in vivo models, single lab","pmids":["40459937"],"is_preprint":false},{"year":2025,"finding":"RONIN (THAP11) interacts with HCF1/HCFC1 to modulate transcriptional activity of TFEB, promoting autophagy and lysosomal activity; RONIN overexpression attenuates D-galactose-induced cochlear hair cell senescence through this TFEB-dependent mechanism.","method":"Co-immunoprecipitation, overexpression, autophagy/lysosomal activity assays, cellular senescence assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP for interaction, gain-of-function with functional readout, single lab, single study","pmids":["39985193"],"is_preprint":false},{"year":2019,"finding":"THAP11 inhibits ubiquitination of p53 mediated by MDM2, thereby increasing p53 protein levels and promoting apoptosis in esophageal cancer cells.","method":"Overexpression, ubiquitination assay, Western blot, flow cytometry","journal":"Journal of Central South University. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression study with ubiquitination assay, no direct mechanistic dissection of how THAP11 inhibits MDM2","pmids":["31969497"],"is_preprint":false},{"year":2025,"finding":"THAP11 interacts with PRRSV Nsp1β protein and promotes its degradation via K48- and K63-linked ubiquitination, restricting viral replication; overexpression of THAP11 reduced PRRSV N protein accumulation while knockdown increased replication.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, ubiquitination assays, overexpression/knockdown","journal":"Cellular and molecular life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay in a porcine virus context, unclear relevance to canonical mammalian THAP11 function, single lab","pmids":["40548980"],"is_preprint":false},{"year":2014,"finding":"Expansion of polyQ repeats in THAP11 (38Q vs 29Q) causes formation of intranuclear inclusions in PC12 cells, G0/G1 cell-cycle arrest, and inhibition of CREB-mediated transcription; TBP, CBP, and HSP70 are recruited to THAP11(38Q) aggregates.","method":"Fluorescence confocal imaging, cell growth/cell-cycle assays, transcription reporter assays, co-localization","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — cellular imaging with functional readouts in neuronal cell line, multiple phenotypic endpoints, single lab","pmids":["24677642"],"is_preprint":false}],"current_model":"THAP11 (Ronin) is a THAP domain-containing, sequence-specific DNA-binding transcription factor that forms an obligate complex with the coregulator HCF-1 (HCFC1) and the zinc-finger protein ZNF143 at CpG-island promoters bearing an ACTACA motif, where it bidirectionally regulates transcription of genes controlling protein biosynthesis, energy metabolism, ribosome biogenesis, mitochondrial electron transport, cell-cycle progression, DNA repair, and cobalamin metabolism (via MMACHC); its C-terminal domain forms a parallel homodimeric coiled-coil, and pathological CAG-repeat expansion produces toxic polyQ aggregates that cause gain-of-function cerebellar neurodegeneration (SCA51) partly through TREM2-mediated microglial activation."},"narrative":{"mechanistic_narrative":"THAP11 (Ronin) is a sequence-specific, THAP-domain DNA-binding transcription factor that forms a mutually dependent complex with the coregulator HCF-1 (HCFC1) and the zinc-finger protein ZNF143 at active CpG-island promoters, where it bidirectionally controls genes governing protein biosynthesis, energy metabolism, and cell-cycle progression [PMID:18585351, PMID:22371484, PMID:23539139]. Recruitment of the complex is directed by an ACTACA submotif shared with ZNF143, whose position and spacing relative to the ZNF143 core motif determine THAP11/HCFC1 occupancy, target transcription, and local histone modification [PMID:26416877]; the complex is mutually interdependent, with HCF-1 chromatin association requiring THAP11 (and ZNF143) and vice versa [PMID:22371484, PMID:25437553]. Through this circuitry THAP11 transcriptionally activates ribosomal protein and mitochondrial electron transport chain genes to support ribosome biogenesis and energy production [PMID:26876175, PMID:35013307], drives cell-cycle progression and proliferation at E2F-bound promoters [PMID:25437553], and represses c-Myc in a DNA-binding-dependent manner with c-Myc as a downstream effector of its growth-suppressive activity [PMID:19008924]. These functions underlie its requirement for embryonic stem cell self-renewal and pluripotency [PMID:18585351, PMID:34515391] and for progenitor proliferation and DNA-damage responses in vivo [PMID:26876175, PMID:28715716]. THAP11 and HCFC1 jointly regulate MMACHC, and a THAP11 point mutation reduces MMACHC expression to cause cobalamin metabolic defects [PMID:28449119]. The C-terminal region forms a left-handed parallel homodimeric coiled-coil [PMID:26975212]. Pathologically, CAG-repeat expansion in THAP11 causes the cerebellar ataxia SCA51: the expanded polyQ protein aggregates and exerts length-dependent gain-of-function neurodegeneration, in part by transcriptionally upregulating TREM2 to activate microglia [PMID:37148549, PMID:40459937].","teleology":[{"year":2008,"claim":"Established THAP11 as a physical partner of the transcriptional coregulator HCF-1 and tied that interaction to a defined cellular program — stem cell self-renewal — defining its core biological role.","evidence":"Conditional knockout mouse ESC model with gain/loss of function plus direct binding assays","pmids":["18585351"],"confidence":"High","gaps":["Did not resolve direct DNA-binding sites genome-wide","Mechanism by which HCF-1 binding drives self-renewal not defined"]},{"year":2008,"claim":"Identified a specific transcriptional target (c-Myc) repressed by THAP11 in a DNA-binding-dependent manner, providing a molecular handle on its growth-suppressive output.","evidence":"Promoter reporter, ChIP, EMSA, knockdown, and c-Myc rescue in cultured cells","pmids":["19008924"],"confidence":"High","gaps":["Relationship between c-Myc repression and HCF-1-dependent activation programs unclear","Single target focus"]},{"year":2010,"claim":"Defined the genome-wide binding landscape and the ACTACA motif of the Ronin/HCF-1 complex, showing it both activates and represses genes for transcription, splicing, and metabolism.","evidence":"ChIP-seq plus expression profiling","pmids":["20581084"],"confidence":"High","gaps":["Determinants of activation vs repression at individual promoters not resolved","Did not yet incorporate ZNF143"]},{"year":2012,"claim":"Demonstrated reciprocal dependency between THAP11 and HCF-1 for chromatin association and gene regulation, establishing an obligate functional unit rather than a casual interaction.","evidence":"Co-IP, ChIP, and siRNA knockdown with expression profiling in colon cancer cells","pmids":["22371484"],"confidence":"High","gaps":["Did not address whether additional factors stabilize the complex"]},{"year":2012,"claim":"Extended THAP11 beyond transcription to RNA processing by linking it to PCBP1 in control of CD44 alternative splicing and cell invasion.","evidence":"Co-IP, pulldown, domain-deletion mutants, and splicing/invasion assays in hepatoma cells","pmids":["22673507"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between splicing control and the canonical transcriptional complex unclear"]},{"year":2013,"claim":"Showed that THAP11 and ZNF143 co-occupy the vast majority of HCFC1-bound active CpG-island promoters, embedding THAP11 in a broader trimeric recruitment system.","evidence":"ChIP-seq across multiple factors with motif and co-localization analysis in HeLa cells","pmids":["23539139"],"confidence":"High","gaps":["Did not test functional consequences of disrupting co-occupancy"]},{"year":2014,"claim":"Defined the trimeric THAP11/ZNF143/HCF-1 complex on cell-cycle promoters and connected its integrity to proliferation, showing HCF-1 recruitment proceeds via THAP11/ZNF143 rather than E2F.","evidence":"ChIP, reciprocal Co-IP, siRNA knockdown, and cell-cycle/proliferation assays","pmids":["25437553"],"confidence":"High","gaps":["How the complex distinguishes activated from repressed targets unresolved"]},{"year":2015,"claim":"Resolved the cis-regulatory grammar driving recruitment, showing the ACTACA submotif's position and orientation relative to the ZNF143 core motif controls THAP11/HCFC1 occupancy, transcription, and histone marks at endogenous loci.","evidence":"CRISPR-Cas9 endogenous promoter editing and synthetic integrated constructs with ChIP","pmids":["26416877"],"confidence":"High","gaps":["Did not establish which factor first reads the motif","Structural basis of motif recognition not addressed"]},{"year":2016,"claim":"Provided structural insight by solving the C-terminal domain as a parallel homodimeric coiled-coil, indicating THAP11 can self-associate.","evidence":"X-ray crystallography with molecular dynamics and biophysical validation","pmids":["26975212"],"confidence":"High","gaps":["Functional role of dimerization in DNA binding or complex assembly not tested","Full-length structure unresolved"]},{"year":2016,"claim":"Connected THAP11 transcriptional output to mitochondrial bioenergetics, showing it activates electron transport chain genes required for progenitor proliferation.","evidence":"Conditional knockout mouse retinal progenitors with ChIP, ETC activity, ATP, and ROS measurements","pmids":["26876175"],"confidence":"High","gaps":["Whether ETC regulation requires the full trimeric complex not shown"]},{"year":2017,"claim":"Linked THAP11/HCFC1 to cobalamin metabolism via MMACHC regulation and to vertebrate neural development, providing a disease-relevant target gene.","evidence":"Patient sequencing, zebrafish morpholino knockdown, and RNA-seq","pmids":["28449119"],"confidence":"Medium","gaps":["Single lab","Direct binding of THAP11 to MMACHC promoter not fully dissected"]},{"year":2017,"claim":"Implicated THAP11 in the DNA damage response by showing its loss sensitizes ESCs to UV-C with ATR activation and identifying DNA repair target genes.","evidence":"Conditional knockout ESCs with UV-C treatment, ATR pathway assays, and ChIP","pmids":["28715716"],"confidence":"Medium","gaps":["Single study","Direct vs indirect effect on repair genes not separated"]},{"year":2021,"claim":"Consolidated THAP11/HCF-1 as joint regulators of ribosome biogenesis and translation in vivo, integrating ribosomal protein gene control with metabolic and MMACHC phenotypes.","evidence":"Hcfc1 and Ronin mutant mouse models with RNA-seq, ribosome biogenesis, and metabolic assays","pmids":["35013307"],"confidence":"High","gaps":["Mechanism coupling ribosome and cobalamin defects unclear"]},{"year":2021,"claim":"Showed Ronin tunes energy production and ribosomal gene expression to maintain the proliferative pluripotent state, with its loss inducing reversible quiescence and disorganized lineage architecture.","evidence":"Conditional knockout mouse embryos with metabolic assays, expression profiling, and morphology","pmids":["34515391"],"confidence":"Medium","gaps":["Single lab","Direct targets driving quiescence not pinpointed"]},{"year":2021,"claim":"First connected dysregulated Ronin levels to cerebellar disease, showing transgenic overexpression in Purkinje cells causes ataxia and deregulates SCA-associated genes bearing Ronin motifs.","evidence":"Transgenic mouse model with motif-based target analysis and Western blot","pmids":["34165550"],"confidence":"Medium","gaps":["Causal target genes for ataxia not established","Overexpression model may not reflect endogenous pathology"]},{"year":2014,"claim":"Provided early evidence that polyQ expansion in THAP11 is cytotoxic, forming intranuclear inclusions and disrupting CREB-mediated transcription.","evidence":"Confocal imaging, cell-cycle and transcription reporter assays in PC12 cells","pmids":["24677642"],"confidence":"Medium","gaps":["Repeat lengths tested below clinical threshold","In vivo relevance not established"]},{"year":2023,"claim":"Established CAG-repeat expansion in THAP11 as the genetic cause of SCA51, with length-dependent aggregation and cytoplasmic redistribution of the polyQ protein.","evidence":"Long-read whole-genome sequencing, linkage in two pedigrees, and aggregation imaging in patient fibroblasts and Neuro-2a cells","pmids":["37148549"],"confidence":"Medium","gaps":["Mechanism of toxicity not yet defined","Whether normal transcriptional function is lost or altered unclear"]},{"year":2025,"claim":"Defined a gain-of-function neurodegenerative mechanism for SCA51 in which aggregated mutant THAP11 upregulates TREM2 to activate microglia, with TREM2 loss or microglial depletion rescuing the phenotype.","evidence":"SCA51 knockin mice, viral expression in mouse/monkey brain, TREM2 knockout/depletion, and histology","pmids":["40459937"],"confidence":"High","gaps":["How aggregated THAP11 drives TREM2 transcription mechanistically unclear","Contribution of lost wild-type function not separated"]},{"year":2025,"claim":"Extended the THAP11/HCF-1 axis to autophagy regulation, showing it modulates TFEB transcriptional activity to attenuate cellular senescence.","evidence":"Co-IP, overexpression, and autophagy/lysosomal/senescence assays in cochlear hair cells","pmids":["39985193"],"confidence":"Medium","gaps":["Single study","Direct vs indirect effect on TFEB not resolved"]},{"year":null,"claim":"It remains unresolved how the same THAP11/HCF-1/ZNF143 transcriptional machinery integrates its many target programs and how polyQ expansion converts this factor into a toxic gain-of-function species relative to any loss of its normal transcriptional role.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Mechanism partitioning activation vs repression at target promoters unknown","Relative contribution of toxic gain-of-function vs loss-of-function in SCA51 not separated","Structural basis of DNA and complex recognition by full-length THAP11 undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,7,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16]}],"complexes":["THAP11/HCF-1/ZNF143 complex"],"partners":["HCFC1","ZNF143","PCBP1","TFEB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96EK4","full_name":"THAP domain-containing protein 11","aliases":[],"length_aa":314,"mass_kda":34.5,"function":"Transcription factor, which has both transcriptional activation and repression activities (PubMed:31905202). Also modulates chromatin accessibility (PubMed:38361031). In complex with HCFC1 and ZNF143, regulates the expression of several genes, including AP2S1, ESCO2, OPHN1, RBL1, UBXN8 and ZNF32 (PubMed:26416877). May regulate the expression of genes that encode both cytoplasmic and mitochondrial ribosomal proteins (By similarity). Required for normal mitochondrial development and function. Regulates mitochondrial gene expression, including that of components of the electron transport chain (By similarity). Involved in the maintainance of pluripotency in early embryonic cells, possibly through its action on mitochondrial maturation which is required to meet high energy demands of these cells (By similarity). Required for early development of retina, preventing premature exit of retinal progenitor cells from the cell cycle. This effect may also be mediated by its action on mitochondria (By similarity). Through the regulation of MMACHC gene expression, controls cobalamin metabolism (PubMed:28449119, PubMed:31905202). Required for normal brain development and neural precursor differentiation (By similarity). Involved in cell growth (PubMed:31905202)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96EK4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THAP11","classification":"Not Classified","n_dependent_lines":720,"n_total_lines":1208,"dependency_fraction":0.5960264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/THAP11","total_profiled":1310},"omim":[{"mim_id":"620947","title":"SPINOCEREBELLAR ATAXIA 51; SCA51","url":"https://www.omim.org/entry/620947"},{"mim_id":"620940","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL","url":"https://www.omim.org/entry/620940"},{"mim_id":"609520","title":"THAP DOMAIN-CONTAINING PROTEIN 1; THAP1","url":"https://www.omim.org/entry/609520"},{"mim_id":"609119","title":"THAP DOMAIN-CONTAINING PROTEIN 11; THAP11","url":"https://www.omim.org/entry/609119"},{"mim_id":"300019","title":"HOST CELL FACTOR C1; HCFC1","url":"https://www.omim.org/entry/300019"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/THAP11"},"hgnc":{"alias_symbol":["HRIHFB2206","CTG-B45d","CTG-B43a","RONIN"],"prev_symbol":[]},"alphafold":{"accession":"Q96EK4","domains":[{"cath_id":"-","chopping":"2-85","consensus_level":"medium","plddt":77.0432,"start":2,"end":85}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EK4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EK4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EK4-F1-predicted_aligned_error_v6.png","plddt_mean":67.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THAP11","jax_strain_url":"https://www.jax.org/strain/search?query=THAP11"},"sequence":{"accession":"Q96EK4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96EK4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96EK4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EK4"}},"corpus_meta":[{"pmid":"18585351","id":"PMC_18585351","title":"Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18585351","citation_count":156,"is_preprint":false},{"pmid":"20581084","id":"PMC_20581084","title":"Ronin/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells.","date":"2010","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/20581084","citation_count":99,"is_preprint":false},{"pmid":"23539139","id":"PMC_23539139","title":"HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy.","date":"2013","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/23539139","citation_count":84,"is_preprint":false},{"pmid":"22371484","id":"PMC_22371484","title":"A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22371484","citation_count":56,"is_preprint":false},{"pmid":"28449119","id":"PMC_28449119","title":"Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28449119","citation_count":49,"is_preprint":false},{"pmid":"25437553","id":"PMC_25437553","title":"Host cell factor-1 recruitment to E2F-bound and cell-cycle-control genes is mediated by THAP11 and ZNF143.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25437553","citation_count":47,"is_preprint":false},{"pmid":"37148549","id":"PMC_37148549","title":"CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia.","date":"2023","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/37148549","citation_count":41,"is_preprint":false},{"pmid":"19008924","id":"PMC_19008924","title":"Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc.","date":"2008","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19008924","citation_count":32,"is_preprint":false},{"pmid":"22673507","id":"PMC_22673507","title":"THAP11, a novel binding protein of PCBP1, negatively regulates CD44 alternative splicing and cell invasion in a human hepatoma cell line.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22673507","citation_count":32,"is_preprint":false},{"pmid":"35013307","id":"PMC_35013307","title":"Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013307","citation_count":26,"is_preprint":false},{"pmid":"26876175","id":"PMC_26876175","title":"RONIN Is an Essential Transcriptional Regulator of Genes Required for Mitochondrial Function in the Developing Retina.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26876175","citation_count":26,"is_preprint":false},{"pmid":"26416877","id":"PMC_26416877","title":"Genomic Determinants of THAP11/ZNF143/HCFC1 Complex Recruitment to Chromatin.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26416877","citation_count":21,"is_preprint":false},{"pmid":"39985193","id":"PMC_39985193","title":"RONIN/HCF1-TFEB Axis Protects Against D-Galactose-Induced Cochlear Hair Cell Senescence Through Autophagy Activation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39985193","citation_count":19,"is_preprint":false},{"pmid":"15368101","id":"PMC_15368101","title":"SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies.","date":"2004","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15368101","citation_count":18,"is_preprint":false},{"pmid":"28715716","id":"PMC_28715716","title":"Ronin influences the DNA damage response in pluripotent stem cells.","date":"2017","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28715716","citation_count":10,"is_preprint":false},{"pmid":"34515391","id":"PMC_34515391","title":"Ronin governs the metabolic capacity of the embryonic lineage for post-implantation development.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/34515391","citation_count":10,"is_preprint":false},{"pmid":"24637716","id":"PMC_24637716","title":"Effects of THAP11 on erythroid differentiation and megakaryocytic differentiation of K562 cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24637716","citation_count":9,"is_preprint":false},{"pmid":"32908912","id":"PMC_32908912","title":"THAP11 Functions as a Tumor Suppressor in Gastric Cancer through Regulating c-Myc Signaling Pathways.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32908912","citation_count":9,"is_preprint":false},{"pmid":"21347804","id":"PMC_21347804","title":"The efficacy and safety of reinstitution of tocilizumab in patients with relapsed active rheumatoid arthritis after long-term withdrawal of tocilizumab: retreatment of patients with rheumatoid arthritis with novel anti-IL-6 receptor antibody after a long-term interval following SAMURAI: the RONIN study.","date":"2011","source":"Modern rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/21347804","citation_count":8,"is_preprint":false},{"pmid":"26975212","id":"PMC_26975212","title":"The C-terminal region of the transcriptional regulator THAP11 forms a parallel coiled-coil domain involved in protein dimerization.","date":"2016","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/26975212","citation_count":7,"is_preprint":false},{"pmid":"40459937","id":"PMC_40459937","title":"Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40459937","citation_count":6,"is_preprint":false},{"pmid":"24677642","id":"PMC_24677642","title":"Expansion of the polyQ repeats in THAP11 forms intranuclear aggregation and causes cell G0/G1 arrest.","date":"2014","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/24677642","citation_count":5,"is_preprint":false},{"pmid":"19022753","id":"PMC_19022753","title":"Ronin and caspases in embryonic stem cells: a new perspective on regulation of the pluripotent state.","date":"2008","source":"Cold Spring Harbor symposia on quantitative biology","url":"https://pubmed.ncbi.nlm.nih.gov/19022753","citation_count":5,"is_preprint":false},{"pmid":"34165550","id":"PMC_34165550","title":"Ronin overexpression induces cerebellar degeneration in a mouse model of ataxia.","date":"2021","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/34165550","citation_count":4,"is_preprint":false},{"pmid":"34466492","id":"PMC_34466492","title":"Induced Overexpression of THAP11 in Human Fibroblast Cells Enhances Expression of Key Pluripotency Genes.","date":"2019","source":"Galen medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/34466492","citation_count":3,"is_preprint":false},{"pmid":"40548980","id":"PMC_40548980","title":"THAP11-mediated K48- and K63-linked ubiquitination is essential for the degradation of porcine reproductive and respiratory syndrome virus nonstructural protein 1β.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/40548980","citation_count":1,"is_preprint":false},{"pmid":"31969497","id":"PMC_31969497","title":"[THAP11 mediates the proliferation and apoptosis of esophageal cancer cells via inhibiting ubiquitination of p53].","date":"2019","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31969497","citation_count":1,"is_preprint":false},{"pmid":"33711390","id":"PMC_33711390","title":"THAP11 down-regulation may contribute to cardio-protective effects of sevoflurane anesthesia: Evidence from clinical and molecular evidence.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33711390","citation_count":1,"is_preprint":false},{"pmid":"38943762","id":"PMC_38943762","title":"Generation of human pluripotent stem cell lines (WAe009-A) with THAP11F80L cobalamin disorder-associated mutation.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38943762","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14407,"output_tokens":4750,"usd":0.057236,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12942,"output_tokens":5115,"usd":0.096293,"stage2_stop_reason":"end_turn"},"total_usd":0.153529,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"THAP11 (Ronin) directly binds to HCF-1 (host cell factor 1), a key transcriptional regulator, and this interaction is essential for ES cell self-renewal and pluripotency; conditional knockout of Ronin prevents ES cell growth while forced expression allows proliferation without differentiation.\",\n      \"method\": \"Conditional knockout mouse model, forced overexpression in ES cells, co-immunoprecipitation/direct binding assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, loss-of-function and gain-of-function experiments with defined cellular phenotypes, replicated in subsequent studies\",\n      \"pmids\": [\"18585351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Ronin/HCF-1 complex binds to a hyperconserved enhancer element (ACTACA-containing motif) at promoters of genes involved in transcription initiation, mRNA splicing, and cell metabolism; Ronin/HCF-1 can both repress and activate target genes, with activation of protein biosynthesis and energy production genes predominating.\",\n      \"method\": \"ChIP-seq, genome-wide binding analysis, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with expression profiling, builds on prior Co-IP, replicated by subsequent studies\",\n      \"pmids\": [\"20581084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"THAP11 physically associates with HCF-1 and recruits it to target promoters in human colon cancer cells; THAP11-mediated gene regulation and chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11, indicating mutual dependency.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal dependency shown by ChIP + Co-IP + knockdown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22371484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"THAP11 interacts with PCBP1 (poly(rC)-binding protein 1), and this interaction is required for THAP11 to inhibit CD44 v6 alternative splicing and cell invasion in hepatoma cells; deletion of the PCBP1-binding domain abolishes this regulatory activity.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, overexpression/deletion mutants, CD44 splicing assays, invasion assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner identified by Co-IP, domain deletion confirms requirement, single lab\",\n      \"pmids\": [\"22673507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In human HeLa cells, HCFC1 co-localizes with THAP11 (Ronin) and ZNF143 at ~90% of ~5400 active CpG-island promoters, with the THAP11/ZNF143 binding motif underlying a large fraction of HCFC1 recruitment sites.\",\n      \"method\": \"ChIP-seq, motif analysis, co-localization analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq across multiple factors, independently replicated direction consistent with other labs\",\n      \"pmids\": [\"23539139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"THAP11, ZNF143, and HCF-1 form a mutually dependent trimeric complex on chromatin at E2F-bound and cell-cycle-control gene promoters; HCF-1 recruitment to these promoters is mediated by THAP11 and ZNF143 rather than E2F proteins directly; disruption of this complex reduces cell proliferation, cell-cycle progression, and cell viability.\",\n      \"method\": \"ChIP, Co-immunoprecipitation, siRNA knockdown, cell proliferation and cell-cycle assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, loss-of-function with multiple phenotypic readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"25437553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"THAP11 represses transcription of c-Myc in a DNA binding-dependent manner; THAP11 directly binds the c-Myc promoter as shown by ChIP and EMSA; c-Myc overexpression rescues cells from THAP11-mediated growth suppression, establishing c-Myc as a key downstream effector.\",\n      \"method\": \"Promoter reporter assays, ChIP, EMSA, siRNA knockdown, c-Myc rescue overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro DNA-binding (EMSA), ChIP, promoter reporter, and epistatic rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19008924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ACTACA submotif shared by THAP11 and ZNF143 directs recruitment of THAP11 and HCFC1 to ZNF143-occupied loci; the position, spacing, and orientation of this motif relative to the ZNF143 core motif are critical; CRISPR-Cas9 mutation of the ACTACA submotif at endogenous promoters altered THAP11, ZNF143, and HCFC1 occupancy, gene transcription, and histone modifications.\",\n      \"method\": \"CRISPR-Cas9 endogenous promoter editing, synthetic chromosomally integrated constructs, ChIP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — CRISPR-Cas9 functional genomics with direct chromatin readout, multiple constructs tested, single lab\",\n      \"pmids\": [\"26416877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The C-terminal region of human THAP11 forms a left-handed parallel homo-dimeric coiled-coil structure, as determined by X-ray crystallography, with stability and dynamics validated by molecular dynamics simulations and biophysical experiments.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulation, biophysical experiments (oligomeric state characterization)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved with biophysical validation, single lab but Tier 1 method\",\n      \"pmids\": [\"26975212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RONIN (THAP11) is required for retinal progenitor cell (RPC) proliferation by transcriptionally activating mitochondrial genes including components of electron transport chain complexes I, III, and IV; RPC-specific Ronin loss results in deficient ETC activity, reduced ATP levels, and increased oxidative stress, followed by premature cell-cycle exit.\",\n      \"method\": \"Conditional knockout mouse model, ChIP, gene expression profiling, ETC activity assays, ATP measurements, ROS measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular and metabolic phenotypes, ChIP linking RONIN to target genes, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"26876175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"THAP11 and HCFC1 jointly regulate MMACHC expression, and mutations in THAP11 (p.Phe80Leu) result in reduced MMACHC expression causing cobalamin metabolic defects; THAP11 and HCFC1 regulate proliferation and differentiation of neural precursors in zebrafish, with THAP11 loss causing craniofacial abnormalities.\",\n      \"method\": \"Sanger sequencing, zebrafish morpholino knockdown, RNA-seq, functional assays in developing embryos\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vertebrate model with defined phenotype and overlapping target gene analysis, single lab\",\n      \"pmids\": [\"28449119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional Ronin knockout sensitizes embryonic stem cells to UV-C-induced DNA damage with ATR pathway activation and G2/M arrest; Ronin binds to and transcriptionally regulates DNA repair factor genes including Gtf2h4 and Rad18.\",\n      \"method\": \"Conditional knockout ESCs, UV-C treatment, pathway activation assays (ATR), ChIP, gene expression analysis\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined pathway (ATR) activation and ChIP evidence for target genes, single lab, single study\",\n      \"pmids\": [\"28715716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RONIN (THAP11) and HCF-1 jointly regulate ribosomal protein subunit genes; mouse models with mutations in Hcfc1 and Ronin show reduced ribosomal protein gene expression, ribosome biogenesis defects, translational perturbations, and metabolic defects in addition to loss of Mmachc.\",\n      \"method\": \"Mouse genetic models, RNA-seq, ribosome biogenesis assays, metabolic analyses\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with multiple molecular phenotypes, two regulators genetically linked to same pathway, single lab\",\n      \"pmids\": [\"35013307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ronin is required for active energy production in the embryonic lineage; loss of Ronin results in a reversible quiescent state with promoted naïve pluripotency; Ronin fine-tunes expression of ribosomal protein-encoding genes and is required for tissue-scale organisation of the pluripotent lineage during blastocyst-to-egg-cylinder transition.\",\n      \"method\": \"Conditional knockout mouse model, metabolic assays, gene expression profiling, embryo morphology\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with metabolic and transcriptional readouts, single lab\",\n      \"pmids\": [\"34515391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Transgenic overexpression of Ronin in cerebellar Purkinje cells causes Purkinje cell loss and severe ataxia; several SCA-causing genes harbor Ronin DNA-binding motifs and are transcriptionally deregulated in transgenic animals; ectopic Ronin expression increases Ataxin-1 protein levels in ES cells.\",\n      \"method\": \"Transgenic mouse model, ChIP-based motif analysis, gene expression profiling, Western blot\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transgenic gain-of-function in vivo with motif-based target gene analysis, single lab\",\n      \"pmids\": [\"34165550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAG repeat expansion (45–100 repeats) in THAP11 causes SCA51; expanded THAP11 polyQ protein forms intracellular aggregates, redistributes to the cytoplasm in patient fibroblasts and transfected Neuro-2a cells, and shows length-dependent toxicity correlating with pure CAG repeat number.\",\n      \"method\": \"Long-read whole-genome sequencing, linkage analysis, cell imaging (confocal), transfection of expanded constructs in Neuro-2a cells\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic evidence plus cellular model with aggregation and localization data, replicated in two pedigrees\",\n      \"pmids\": [\"37148549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mutant THAP11 with polyQ expansion causes gain-of-function cerebellar neurodegeneration in mice via protein aggregation; mutant THAP11 transcriptionally upregulates TREM2, activating microglia; loss of TREM2 or microglial depletion mitigates neurodegeneration in SCA51 knockin mice.\",\n      \"method\": \"SCA51 knockin mouse model, viral vector expression in mouse/monkey brains, TREM2 knockout/depletion, gene expression analysis, histology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockin mouse model with genetic epistasis (TREM2 KO rescues phenotype), multiple in vivo models, single lab\",\n      \"pmids\": [\"40459937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RONIN (THAP11) interacts with HCF1/HCFC1 to modulate transcriptional activity of TFEB, promoting autophagy and lysosomal activity; RONIN overexpression attenuates D-galactose-induced cochlear hair cell senescence through this TFEB-dependent mechanism.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, autophagy/lysosomal activity assays, cellular senescence assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP for interaction, gain-of-function with functional readout, single lab, single study\",\n      \"pmids\": [\"39985193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"THAP11 inhibits ubiquitination of p53 mediated by MDM2, thereby increasing p53 protein levels and promoting apoptosis in esophageal cancer cells.\",\n      \"method\": \"Overexpression, ubiquitination assay, Western blot, flow cytometry\",\n      \"journal\": \"Journal of Central South University. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression study with ubiquitination assay, no direct mechanistic dissection of how THAP11 inhibits MDM2\",\n      \"pmids\": [\"31969497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THAP11 interacts with PRRSV Nsp1β protein and promotes its degradation via K48- and K63-linked ubiquitination, restricting viral replication; overexpression of THAP11 reduced PRRSV N protein accumulation while knockdown increased replication.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, ubiquitination assays, overexpression/knockdown\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay in a porcine virus context, unclear relevance to canonical mammalian THAP11 function, single lab\",\n      \"pmids\": [\"40548980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Expansion of polyQ repeats in THAP11 (38Q vs 29Q) causes formation of intranuclear inclusions in PC12 cells, G0/G1 cell-cycle arrest, and inhibition of CREB-mediated transcription; TBP, CBP, and HSP70 are recruited to THAP11(38Q) aggregates.\",\n      \"method\": \"Fluorescence confocal imaging, cell growth/cell-cycle assays, transcription reporter assays, co-localization\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — cellular imaging with functional readouts in neuronal cell line, multiple phenotypic endpoints, single lab\",\n      \"pmids\": [\"24677642\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THAP11 (Ronin) is a THAP domain-containing, sequence-specific DNA-binding transcription factor that forms an obligate complex with the coregulator HCF-1 (HCFC1) and the zinc-finger protein ZNF143 at CpG-island promoters bearing an ACTACA motif, where it bidirectionally regulates transcription of genes controlling protein biosynthesis, energy metabolism, ribosome biogenesis, mitochondrial electron transport, cell-cycle progression, DNA repair, and cobalamin metabolism (via MMACHC); its C-terminal domain forms a parallel homodimeric coiled-coil, and pathological CAG-repeat expansion produces toxic polyQ aggregates that cause gain-of-function cerebellar neurodegeneration (SCA51) partly through TREM2-mediated microglial activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THAP11 (Ronin) is a sequence-specific, THAP-domain DNA-binding transcription factor that forms a mutually dependent complex with the coregulator HCF-1 (HCFC1) and the zinc-finger protein ZNF143 at active CpG-island promoters, where it bidirectionally controls genes governing protein biosynthesis, energy metabolism, and cell-cycle progression [#0, #2, #4]. Recruitment of the complex is directed by an ACTACA submotif shared with ZNF143, whose position and spacing relative to the ZNF143 core motif determine THAP11/HCFC1 occupancy, target transcription, and local histone modification [#7]; the complex is mutually interdependent, with HCF-1 chromatin association requiring THAP11 (and ZNF143) and vice versa [#2, #5]. Through this circuitry THAP11 transcriptionally activates ribosomal protein and mitochondrial electron transport chain genes to support ribosome biogenesis and energy production [#9, #12], drives cell-cycle progression and proliferation at E2F-bound promoters [#5], and represses c-Myc in a DNA-binding-dependent manner with c-Myc as a downstream effector of its growth-suppressive activity [#6]. These functions underlie its requirement for embryonic stem cell self-renewal and pluripotency [#0, #13] and for progenitor proliferation and DNA-damage responses in vivo [#9, #11]. THAP11 and HCFC1 jointly regulate MMACHC, and a THAP11 point mutation reduces MMACHC expression to cause cobalamin metabolic defects [#10]. The C-terminal region forms a left-handed parallel homodimeric coiled-coil [#8]. Pathologically, CAG-repeat expansion in THAP11 causes the cerebellar ataxia SCA51: the expanded polyQ protein aggregates and exerts length-dependent gain-of-function neurodegeneration, in part by transcriptionally upregulating TREM2 to activate microglia [#15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established THAP11 as a physical partner of the transcriptional coregulator HCF-1 and tied that interaction to a defined cellular program — stem cell self-renewal — defining its core biological role.\",\n      \"evidence\": \"Conditional knockout mouse ESC model with gain/loss of function plus direct binding assays\",\n      \"pmids\": [\"18585351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve direct DNA-binding sites genome-wide\", \"Mechanism by which HCF-1 binding drives self-renewal not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a specific transcriptional target (c-Myc) repressed by THAP11 in a DNA-binding-dependent manner, providing a molecular handle on its growth-suppressive output.\",\n      \"evidence\": \"Promoter reporter, ChIP, EMSA, knockdown, and c-Myc rescue in cultured cells\",\n      \"pmids\": [\"19008924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between c-Myc repression and HCF-1-dependent activation programs unclear\", \"Single target focus\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the genome-wide binding landscape and the ACTACA motif of the Ronin/HCF-1 complex, showing it both activates and represses genes for transcription, splicing, and metabolism.\",\n      \"evidence\": \"ChIP-seq plus expression profiling\",\n      \"pmids\": [\"20581084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of activation vs repression at individual promoters not resolved\", \"Did not yet incorporate ZNF143\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated reciprocal dependency between THAP11 and HCF-1 for chromatin association and gene regulation, establishing an obligate functional unit rather than a casual interaction.\",\n      \"evidence\": \"Co-IP, ChIP, and siRNA knockdown with expression profiling in colon cancer cells\",\n      \"pmids\": [\"22371484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether additional factors stabilize the complex\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended THAP11 beyond transcription to RNA processing by linking it to PCBP1 in control of CD44 alternative splicing and cell invasion.\",\n      \"evidence\": \"Co-IP, pulldown, domain-deletion mutants, and splicing/invasion assays in hepatoma cells\",\n      \"pmids\": [\"22673507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between splicing control and the canonical transcriptional complex unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that THAP11 and ZNF143 co-occupy the vast majority of HCFC1-bound active CpG-island promoters, embedding THAP11 in a broader trimeric recruitment system.\",\n      \"evidence\": \"ChIP-seq across multiple factors with motif and co-localization analysis in HeLa cells\",\n      \"pmids\": [\"23539139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test functional consequences of disrupting co-occupancy\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the trimeric THAP11/ZNF143/HCF-1 complex on cell-cycle promoters and connected its integrity to proliferation, showing HCF-1 recruitment proceeds via THAP11/ZNF143 rather than E2F.\",\n      \"evidence\": \"ChIP, reciprocal Co-IP, siRNA knockdown, and cell-cycle/proliferation assays\",\n      \"pmids\": [\"25437553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the complex distinguishes activated from repressed targets unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the cis-regulatory grammar driving recruitment, showing the ACTACA submotif's position and orientation relative to the ZNF143 core motif controls THAP11/HCFC1 occupancy, transcription, and histone marks at endogenous loci.\",\n      \"evidence\": \"CRISPR-Cas9 endogenous promoter editing and synthetic integrated constructs with ChIP\",\n      \"pmids\": [\"26416877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which factor first reads the motif\", \"Structural basis of motif recognition not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided structural insight by solving the C-terminal domain as a parallel homodimeric coiled-coil, indicating THAP11 can self-associate.\",\n      \"evidence\": \"X-ray crystallography with molecular dynamics and biophysical validation\",\n      \"pmids\": [\"26975212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of dimerization in DNA binding or complex assembly not tested\", \"Full-length structure unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected THAP11 transcriptional output to mitochondrial bioenergetics, showing it activates electron transport chain genes required for progenitor proliferation.\",\n      \"evidence\": \"Conditional knockout mouse retinal progenitors with ChIP, ETC activity, ATP, and ROS measurements\",\n      \"pmids\": [\"26876175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ETC regulation requires the full trimeric complex not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked THAP11/HCFC1 to cobalamin metabolism via MMACHC regulation and to vertebrate neural development, providing a disease-relevant target gene.\",\n      \"evidence\": \"Patient sequencing, zebrafish morpholino knockdown, and RNA-seq\",\n      \"pmids\": [\"28449119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct binding of THAP11 to MMACHC promoter not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated THAP11 in the DNA damage response by showing its loss sensitizes ESCs to UV-C with ATR activation and identifying DNA repair target genes.\",\n      \"evidence\": \"Conditional knockout ESCs with UV-C treatment, ATR pathway assays, and ChIP\",\n      \"pmids\": [\"28715716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Direct vs indirect effect on repair genes not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated THAP11/HCF-1 as joint regulators of ribosome biogenesis and translation in vivo, integrating ribosomal protein gene control with metabolic and MMACHC phenotypes.\",\n      \"evidence\": \"Hcfc1 and Ronin mutant mouse models with RNA-seq, ribosome biogenesis, and metabolic assays\",\n      \"pmids\": [\"35013307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling ribosome and cobalamin defects unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed Ronin tunes energy production and ribosomal gene expression to maintain the proliferative pluripotent state, with its loss inducing reversible quiescence and disorganized lineage architecture.\",\n      \"evidence\": \"Conditional knockout mouse embryos with metabolic assays, expression profiling, and morphology\",\n      \"pmids\": [\"34515391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct targets driving quiescence not pinpointed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"First connected dysregulated Ronin levels to cerebellar disease, showing transgenic overexpression in Purkinje cells causes ataxia and deregulates SCA-associated genes bearing Ronin motifs.\",\n      \"evidence\": \"Transgenic mouse model with motif-based target analysis and Western blot\",\n      \"pmids\": [\"34165550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal target genes for ataxia not established\", \"Overexpression model may not reflect endogenous pathology\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided early evidence that polyQ expansion in THAP11 is cytotoxic, forming intranuclear inclusions and disrupting CREB-mediated transcription.\",\n      \"evidence\": \"Confocal imaging, cell-cycle and transcription reporter assays in PC12 cells\",\n      \"pmids\": [\"24677642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Repeat lengths tested below clinical threshold\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established CAG-repeat expansion in THAP11 as the genetic cause of SCA51, with length-dependent aggregation and cytoplasmic redistribution of the polyQ protein.\",\n      \"evidence\": \"Long-read whole-genome sequencing, linkage in two pedigrees, and aggregation imaging in patient fibroblasts and Neuro-2a cells\",\n      \"pmids\": [\"37148549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of toxicity not yet defined\", \"Whether normal transcriptional function is lost or altered unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a gain-of-function neurodegenerative mechanism for SCA51 in which aggregated mutant THAP11 upregulates TREM2 to activate microglia, with TREM2 loss or microglial depletion rescuing the phenotype.\",\n      \"evidence\": \"SCA51 knockin mice, viral expression in mouse/monkey brain, TREM2 knockout/depletion, and histology\",\n      \"pmids\": [\"40459937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How aggregated THAP11 drives TREM2 transcription mechanistically unclear\", \"Contribution of lost wild-type function not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the THAP11/HCF-1 axis to autophagy regulation, showing it modulates TFEB transcriptional activity to attenuate cellular senescence.\",\n      \"evidence\": \"Co-IP, overexpression, and autophagy/lysosomal/senescence assays in cochlear hair cells\",\n      \"pmids\": [\"39985193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Direct vs indirect effect on TFEB not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the same THAP11/HCF-1/ZNF143 transcriptional machinery integrates its many target programs and how polyQ expansion converts this factor into a toxic gain-of-function species relative to any loss of its normal transcriptional role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism partitioning activation vs repression at target promoters unknown\", \"Relative contribution of toxic gain-of-function vs loss-of-function in SCA51 not separated\", \"Structural basis of DNA and complex recognition by full-length THAP11 undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"complexes\": [\"THAP11/HCF-1/ZNF143 complex\"],\n    \"partners\": [\"HCFC1\", \"ZNF143\", \"PCBP1\", \"TFEB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}