Affinage

THAP11

THAP domain-containing protein 11 · UniProt Q96EK4

Length
314 aa
Mass
34.5 kDa
Annotated
2026-06-10
29 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2008 High

    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

    PMID:18585351

    Open questions at the time
    • Did not resolve direct DNA-binding sites genome-wide
    • Mechanism by which HCF-1 binding drives self-renewal not defined
  2. 2008 High

    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

    PMID:19008924

    Open questions at the time
    • Relationship between c-Myc repression and HCF-1-dependent activation programs unclear
    • Single target focus
  3. 2010 High

    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

    PMID:20581084

    Open questions at the time
    • Determinants of activation vs repression at individual promoters not resolved
    • Did not yet incorporate ZNF143
  4. 2012 High

    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

    PMID:22371484

    Open questions at the time
    • Did not address whether additional factors stabilize the complex
  5. 2012 Medium

    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

    PMID:22673507

    Open questions at the time
    • Single lab
    • Mechanistic link between splicing control and the canonical transcriptional complex unclear
  6. 2013 High

    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

    PMID:23539139

    Open questions at the time
    • Did not test functional consequences of disrupting co-occupancy
  7. 2014 High

    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

    PMID:25437553

    Open questions at the time
    • How the complex distinguishes activated from repressed targets unresolved
  8. 2015 High

    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

    PMID:26416877

    Open questions at the time
    • Did not establish which factor first reads the motif
    • Structural basis of motif recognition not addressed
  9. 2016 High

    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

    PMID:26975212

    Open questions at the time
    • Functional role of dimerization in DNA binding or complex assembly not tested
    • Full-length structure unresolved
  10. 2016 High

    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

    PMID:26876175

    Open questions at the time
    • Whether ETC regulation requires the full trimeric complex not shown
  11. 2017 Medium

    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

    PMID:28449119

    Open questions at the time
    • Single lab
    • Direct binding of THAP11 to MMACHC promoter not fully dissected
  12. 2017 Medium

    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

    PMID:28715716

    Open questions at the time
    • Single study
    • Direct vs indirect effect on repair genes not separated
  13. 2021 High

    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

    PMID:35013307

    Open questions at the time
    • Mechanism coupling ribosome and cobalamin defects unclear
  14. 2021 Medium

    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

    PMID:34515391

    Open questions at the time
    • Single lab
    • Direct targets driving quiescence not pinpointed
  15. 2021 Medium

    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

    PMID:34165550

    Open questions at the time
    • Causal target genes for ataxia not established
    • Overexpression model may not reflect endogenous pathology
  16. 2014 Medium

    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

    PMID:24677642

    Open questions at the time
    • Repeat lengths tested below clinical threshold
    • In vivo relevance not established
  17. 2023 Medium

    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

    PMID:37148549

    Open questions at the time
    • Mechanism of toxicity not yet defined
    • Whether normal transcriptional function is lost or altered unclear
  18. 2025 High

    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

    PMID:40459937

    Open questions at the time
    • How aggregated THAP11 drives TREM2 transcription mechanistically unclear
    • Contribution of lost wild-type function not separated
  19. 2025 Medium

    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

    PMID:39985193

    Open questions at the time
    • Single study
    • Direct vs indirect effect on TFEB not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 2 R-HSA-1640170 Cell Cycle 1 R-HSA-8953854 Metabolism of RNA 1
Partners
HCFC1PCBP1TFEBZNF143
Complex memberships
THAP11/HCF-1/ZNF143 complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. Conditional knockout mouse model, forced overexpression in ES cells, co-immunoprecipitation/direct binding assay Cell High 18585351
2010 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. ChIP-seq, genome-wide binding analysis, gene expression profiling Genes & development High 20581084
2012 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. Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression profiling Molecular and cellular biology High 22371484
2012 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. Co-immunoprecipitation, pulldown, overexpression/deletion mutants, CD44 splicing assays, invasion assays FEBS letters Medium 22673507
2013 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. ChIP-seq, motif analysis, co-localization analysis Genome research High 23539139
2014 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. ChIP, Co-immunoprecipitation, siRNA knockdown, cell proliferation and cell-cycle assays Cell reports High 25437553
2008 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. Promoter reporter assays, ChIP, EMSA, siRNA knockdown, c-Myc rescue overexpression Cell death and differentiation High 19008924
2015 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. CRISPR-Cas9 endogenous promoter editing, synthetic chromosomally integrated constructs, ChIP Molecular and cellular biology High 26416877
2016 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. X-ray crystallography, molecular dynamics simulation, biophysical experiments (oligomeric state characterization) Journal of structural biology High 26975212
2016 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. Conditional knockout mouse model, ChIP, gene expression profiling, ETC activity assays, ATP measurements, ROS measurements Cell reports High 26876175
2017 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. Sanger sequencing, zebrafish morpholino knockdown, RNA-seq, functional assays in developing embryos Human molecular genetics Medium 28449119
2017 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. Conditional knockout ESCs, UV-C treatment, pathway activation assays (ATR), ChIP, gene expression analysis Stem cell research Medium 28715716
2021 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. Mouse genetic models, RNA-seq, ribosome biogenesis assays, metabolic analyses Nature communications High 35013307
2021 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. Conditional knockout mouse model, metabolic assays, gene expression profiling, embryo morphology EMBO reports Medium 34515391
2021 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. Transgenic mouse model, ChIP-based motif analysis, gene expression profiling, Western blot Disease models & mechanisms Medium 34165550
2023 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. Long-read whole-genome sequencing, linkage analysis, cell imaging (confocal), transfection of expanded constructs in Neuro-2a cells Movement disorders Medium 37148549
2025 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. SCA51 knockin mouse model, viral vector expression in mouse/monkey brains, TREM2 knockout/depletion, gene expression analysis, histology The Journal of clinical investigation High 40459937
2025 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. Co-immunoprecipitation, overexpression, autophagy/lysosomal activity assays, cellular senescence assays Advanced science Medium 39985193
2019 THAP11 inhibits ubiquitination of p53 mediated by MDM2, thereby increasing p53 protein levels and promoting apoptosis in esophageal cancer cells. Overexpression, ubiquitination assay, Western blot, flow cytometry Journal of Central South University. Medical sciences Low 31969497
2025 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. Yeast two-hybrid, co-immunoprecipitation, co-localization, ubiquitination assays, overexpression/knockdown Cellular and molecular life sciences Low 40548980
2014 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. Fluorescence confocal imaging, cell growth/cell-cycle assays, transcription reporter assays, co-localization Cell biology international Medium 24677642

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 156 18585351
2010 Ronin/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells. Genes & development 99 20581084
2013 HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy. Genome research 84 23539139
2012 A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function. Molecular and cellular biology 56 22371484
2017 Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities. Human molecular genetics 49 28449119
2014 Host cell factor-1 recruitment to E2F-bound and cell-cycle-control genes is mediated by THAP11 and ZNF143. Cell reports 47 25437553
2023 CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia. Movement disorders : official journal of the Movement Disorder Society 41 37148549
2012 THAP11, a novel binding protein of PCBP1, negatively regulates CD44 alternative splicing and cell invasion in a human hepatoma cell line. FEBS letters 32 22673507
2008 Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc. Cell death and differentiation 32 19008924
2022 Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy. Nature communications 26 35013307
2016 RONIN Is an Essential Transcriptional Regulator of Genes Required for Mitochondrial Function in the Developing Retina. Cell reports 26 26876175
2015 Genomic Determinants of THAP11/ZNF143/HCFC1 Complex Recruitment to Chromatin. Molecular and cellular biology 21 26416877
2025 RONIN/HCF1-TFEB Axis Protects Against D-Galactose-Induced Cochlear Hair Cell Senescence Through Autophagy Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 39985193
2004 SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies. Journal of human genetics 18 15368101
2021 Ronin governs the metabolic capacity of the embryonic lineage for post-implantation development. EMBO reports 10 34515391
2017 Ronin influences the DNA damage response in pluripotent stem cells. Stem cell research 10 28715716
2020 THAP11 Functions as a Tumor Suppressor in Gastric Cancer through Regulating c-Myc Signaling Pathways. BioMed research international 9 32908912
2014 Effects of THAP11 on erythroid differentiation and megakaryocytic differentiation of K562 cells. PloS one 9 24637716
2011 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. Modern rheumatology 8 21347804
2016 The C-terminal region of the transcriptional regulator THAP11 forms a parallel coiled-coil domain involved in protein dimerization. Journal of structural biology 7 26975212
2025 Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice. The Journal of clinical investigation 6 40459937
2014 Expansion of the polyQ repeats in THAP11 forms intranuclear aggregation and causes cell G0/G1 arrest. Cell biology international 5 24677642
2008 Ronin and caspases in embryonic stem cells: a new perspective on regulation of the pluripotent state. Cold Spring Harbor symposia on quantitative biology 5 19022753
2021 Ronin overexpression induces cerebellar degeneration in a mouse model of ataxia. Disease models & mechanisms 4 34165550
2019 Induced Overexpression of THAP11 in Human Fibroblast Cells Enhances Expression of Key Pluripotency Genes. Galen medical journal 3 34466492
2025 THAP11-mediated K48- and K63-linked ubiquitination is essential for the degradation of porcine reproductive and respiratory syndrome virus nonstructural protein 1β. Cellular and molecular life sciences : CMLS 1 40548980
2021 THAP11 down-regulation may contribute to cardio-protective effects of sevoflurane anesthesia: Evidence from clinical and molecular evidence. Life sciences 1 33711390
2019 [THAP11 mediates the proliferation and apoptosis of esophageal cancer cells via inhibiting ubiquitination of p53]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 1 31969497
2024 Generation of human pluripotent stem cell lines (WAe009-A) with THAP11F80L cobalamin disorder-associated mutation. Stem cell research 0 38943762

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