Affinage

THAP1

THAP domain-containing protein 1 · UniProt Q9NVV9

Length
213 aa
Mass
24.9 kDa
Annotated
2026-06-10
83 papers in source corpus 30 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THAP1 is a zinc-dependent, sequence-specific DNA-binding transcription factor that controls cell proliferation, differentiation, and survival through direct occupancy of defined promoter elements (PMID:15863623, PMID:17003378). DNA recognition is mediated by an N-terminal atypical THAP zinc finger of ~80 residues that folds as an antiparallel beta-sheet with a loop-helix-loop insertion contacting an 11-nucleotide consensus, and that requires both zinc coordination through its C2CH motif and a positively charged lysine/arginine surface (PMID:15863623, PMID:18073205). THAP1 acts within multiprotein transcriptional complexes: it recruits the coactivator HCF-1 (and associated OGT) to the RRM1 promoter to drive pRB/E2F-dependent cell-cycle gene expression and endothelial proliferation (PMID:17003378, PMID:20200153), represses the dystonia gene TOR1A and autoregulates its own promoter (PMID:20976771, PMID:20865765, PMID:25088175), and activates SOD2 and the proteasome subunit gene PSMB5 — the latter sustaining proteasome assembly and clearance of ubiquitinated proteins (PMID:32112337, PMID:39952963, PMID:39929834). Much of its transcriptional output is indirect, channeled through control of the SP1/SP4 family in a cell-type-dependent manner (PMID:35015830). In the oligodendrocyte lineage THAP1 partners with YY1 to time CNS myelination cell-autonomously, in part by regulating lysosomal glycosaminoglycan catabolism via the β-glucuronidase gene GusB (PMID:28697333, PMID:34312226, PMID:34686877). THAP1 also balances DNA double-strand break repair pathway choice by binding the SHLD1 promoter together with YY1 and HCF1 to restrain Shieldin expression (PMID:33857404), drives apoptosis through interaction with Par-4 at PML nuclear bodies and at the CCAR1 promoter (PMID:12717420, PMID:23975424), and acts as a maternal-effect factor activating Rrm1 to supply dNTPs for zygotic genome activation (PMID:41731150). The protein homodimerizes through a C-terminal coiled-coil region (aa 139–185) (PMID:21752024, PMID:28299530). Dominant DYT6 dystonia is caused by THAP1 mutations that act through heterogeneous mechanisms — impaired DNA binding, reduced protein thermostability, loss of autoregulation, disrupted YY1 co-recruitment, or defective nuclear import — converging on transcriptional dysregulation (PMID:19182804, PMID:22844099, PMID:25088175, PMID:34686877).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 Medium

    Established THAP1's first cellular role by showing it is a nuclear proapoptotic factor, placing it in PML nuclear bodies and physically linked to Par-4 before any DNA-binding function was known.

    Evidence Co-localization, domain-deletion analysis, and apoptosis assays in primary endothelial cells and fibroblasts

    PMID:12717420

    Open questions at the time
    • Did not identify direct transcriptional targets
    • THAP domain shown dispensable for Par-4 binding but required for apoptosis without mechanism
    • Single lab co-localization
  2. 2005 High

    Defined the molecular activity of THAP1 by demonstrating the THAP domain is a zinc-dependent sequence-specific DNA-binding module with an 11-nucleotide consensus, converting an apoptosis factor into a candidate transcription factor.

    Evidence In vitro binding-site selection, zinc chelation, and site-directed mutagenesis

    PMID:15863623

    Open questions at the time
    • No in vivo target gene identified
    • No structural model of domain
    • Did not address transcriptional activation versus repression
  3. 2006 High

    Connected DNA binding to physiological output by identifying RRM1 as a direct in vivo target and placing THAP1 in pRB/E2F-dependent control of G1/S progression and endothelial proliferation.

    Evidence ChIP for promoter occupancy plus reciprocal overexpression and RNAi with proliferation readout

    PMID:17003378

    Open questions at the time
    • Did not identify coactivators recruited
    • Mechanism of pRB/E2F target regulation indirect
    • Restricted to endothelial cells
  4. 2007 High

    Resolved how THAP1 recognizes DNA by determining the NMR structure of the atypical zinc finger and mapping the loop-helix-loop DNA-binding interface.

    Evidence Multidimensional NMR, alanine scanning, and chemical shift perturbation

    PMID:18073205

    Open questions at the time
    • No co-structure with DNA
    • C-terminal coiled-coil not structurally characterized
    • Did not address full-length protein behavior
  5. 2009 Medium

    Provided the first disease mechanism by showing a DYT6 missense mutation in the DNA-binding domain abolishes DNA binding, framing dystonia as transcriptional dysregulation.

    Evidence Functional DNA-binding assay of a disease mutation

    PMID:19182804

    Open questions at the time
    • Single mutation tested
    • Did not establish which target genes are affected
    • No in vivo confirmation
  6. 2010 High

    Identified the coactivator machinery THAP1 uses and a key repressed target, showing THAP1 recruits HCF-1/OGT to activate RRM1 and directly represses the dystonia gene TOR1A.

    Evidence Mass spectrometry, reciprocal co-IP, ChIP, and RNAi (HCF-1/OGT); EMSA, ChIP-qPCR, and luciferase reporters (TOR1A), with independent replication

    PMID:20200153 PMID:20865765 PMID:20976771

    Open questions at the time
    • How activation versus repression is determined at different promoters unresolved
    • OGT functional contribution not dissected
    • Link between TOR1A repression and dystonia phenotype not tested in vivo
  7. 2011 Medium

    Showed THAP1 homodimerizes through a C-terminal coiled-coil, and that a frameshift removing this region abolishes self-association while subcellular mislocalization defines another mutation class.

    Evidence Co-IP and deletion mapping (dimerization); immunofluorescence of transfected cells (mislocalization)

    PMID:21752024 PMID:21847143

    Open questions at the time
    • Functional consequence of dimerization for transcription not established
    • Mislocalization shown in overexpression only
    • Most DYT6 mutations do not affect dimerization, leaving their mechanism open
  8. 2012 High

    Reframed DYT6 pathogenesis by showing most THAP-domain missense mutations do not abolish DNA binding but instead destabilize the folded protein below physiological temperature.

    Evidence NMR, fluorescence, differential scanning fluorimetry, and ITC across multiple mutations; immunofluorescence localization of truncations

    PMID:22652465 PMID:22844099

    Open questions at the time
    • Thermostability measured in vitro, not in cells
    • Did not test whether destabilized protein is degraded in vivo
    • Localization data from overexpression in non-neuronal cells
  9. 2013 Medium

    Extended the Par-4 partnership into transcriptional and splicing control, showing the Par-4/THAP1 complex binds the CCAR1 promoter and antagonizes Notch3 to govern alternative splicing and T-ALL survival.

    Evidence Co-IP, ChIP, luciferase reporter, and splicing analysis

    PMID:23975424

    Open questions at the time
    • Splicing regulation mechanism via SRp40/SRp55 not fully resolved
    • Single cancer-cell context
    • Relationship to canonical THAP1 transcriptional targets unclear
  10. 2014 Medium

    Established negative autoregulation and protein turnover as control mechanisms, showing THAP1 represses its own promoter, is degraded by the proteasome, and exists as neuron-specific protein species.

    Evidence Luciferase reporters, quantitative ChIP, RT-qPCR, and proteasome inhibition; Western blot, IP, and subcellular fractionation across tissues

    PMID:25088175 PMID:25231164

    Open questions at the time
    • Identity of neuron-specific post-translational modifications unknown
    • Ubiquitin ligase mediating degradation not identified
    • Functional role of distinct isoforms untested
  11. 2017 High

    Defined THAP1's developmental functions in vivo, showing it is required cell-autonomously for oligodendrocyte maturation and myelination timing via YY1, and for embryonic stem cell survival and neuroectodermal differentiation.

    Evidence Conditional knockout mice with OL purification and ChIP (myelination); knockout/knock-in ESCs with ChIP-Seq (differentiation)

    PMID:28579396 PMID:28697333

    Open questions at the time
    • Direct versus indirect target genes not fully separated
    • Mechanism of YY1 co-occupancy unresolved at this stage
    • Link to dystonia phenotype not yet established
  12. 2018 Medium

    Linked THAP1 dysfunction to specific neuronal pathways in vivo, showing heterozygous dystonia alleles dysregulate eIF2α signaling and synaptic pathways with electrophysiological deficits partially rescued pharmacologically.

    Evidence In vivo RNA-Seq of mouse striatum/cerebellum, electrophysiology, neurite outgrowth, and salubrinal rescue

    PMID:29364887

    Open questions at the time
    • Direct THAP1 targets among dysregulated genes not defined
    • Tissue- and genotype-dependent effects mechanistically unexplained
    • salubrinal rescue only partial
  13. 2020 Medium

    Added oxidative-stress defense to THAP1's regulon by showing direct SOD2 promoter binding with dose-dependent expression control, and reinforced that disease mutations reduce protein stability.

    Evidence ChIP-seq, expression profiling, Western blot, and patient fibroblast analysis

    PMID:32112337

    Open questions at the time
    • Physiological consequence of altered SOD2 not tested
    • Single lab
    • Cofactor requirements at SOD2 promoter unknown
  14. 2021 High

    Diversified THAP1's mechanistic repertoire across DNA repair, myelination metabolism, neuronal excitability, and SP1/SP4-mediated gene control, while resolving that most THAP1 transcriptional output is indirect.

    Evidence ChIP and PARP-inhibitor genetics (SHLD1); knockout OPCs with ChIP and GAG/GusB rescue; patient iPSC neurons with patch-clamp; iPSC allelic series with RNA-Seq and mouse myelin histology; ChIP-seq/RNA-seq across multiple models (SP1/SP4)

    PMID:33857404 PMID:34095114 PMID:34312226 PMID:34672987 PMID:35015830

    Open questions at the time
    • How a single factor selects among repair, metabolic, and neuronal programs unclear
    • Determinants of direct versus SP1/SP4-indirect regulation undefined
    • Causal chain from transcriptional changes to dystonia behavior incomplete
  15. 2022 High

    Defined a transcription-complex-assembly mechanism for disease by showing the DYT6 F81L mutant binds DNA normally yet fails to co-recruit YY1, disrupting myelination.

    Evidence Knock-in mouse with ChIP for THAP1 and YY1 occupancy, myelination and reporter assays

    PMID:34686877

    Open questions at the time
    • Structural basis of THAP1–YY1 cooperativity unknown
    • Whether other DYT6 mutations share this mechanism not tested here
    • Direct biochemical THAP1–YY1 interaction not demonstrated
  16. 2025 High

    Revealed an essential proteostasis function, showing THAP1 directly drives PSMB5 expression to sustain proteasome assembly and prevent toxic ubiquitinated-protein accumulation.

    Evidence Genome-wide coessentiality screen, depletion with proteasome activity assays, PSMB5 promoter binding, and deep mutational scanning, across two independent reports

    PMID:39929834 PMID:39952963

    Open questions at the time
    • Tissue specificity of proteasome dependence unexplored
    • Relationship between proteasome control and dystonia phenotypes unknown
    • Cofactors at PSMB5 promoter not defined
  17. 2026 High

    Identified a maternal-effect role, showing oocyte THAP1 activates Rrm1 to supply dNTPs required for zygotic genome activation and early embryonic progression.

    Evidence Oocyte-specific conditional knockout, low-input metabolomics, RNA-seq, and Rrm1 mRNA rescue

    PMID:41731150

    Open questions at the time
    • Whether RRM1 control is conserved in somatic THAP1 functions not addressed
    • Other maternal targets not mapped
    • Link to human reproductive phenotypes unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How THAP1 selects among its diverse promoter targets and decides between activation and repression, direct versus SP1/SP4-mediated control, and which cofactor (HCF-1, YY1, Par-4, OGT) is engaged in a given cellular context remains unresolved.
  • No unifying model linking context to cofactor choice
  • Causal chain from specific transcriptional changes to DYT6 dystonia incomplete
  • Genome-wide direct binding versus functional output discordance unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 7 GO:0140110 transcription regulator activity 6
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-392499 Metabolism of proteins 1 R-HSA-73894 DNA Repair 1
Partners
HCF1OGTPAWRSP1SP4YY1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 The THAP domain of THAP1 is a zinc-dependent sequence-specific DNA-binding domain. In vitro binding-site selection identified an 11-nucleotide consensus DNA-binding sequence. Mutations of single nucleotide positions in this sequence abrogated binding. The zinc chelator 1,10-o-phenanthroline abolished DNA binding, and site-directed mutagenesis of cysteine or histidine residues in the C2CH motif impaired zinc coordination and DNA binding. Four conserved residues (P, W, F, and P) were also required for DNA binding. In vitro binding-site selection, zinc chelation, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 15863623
2003 THAP1 is a nuclear proapoptotic factor that localizes to PML nuclear bodies and interacts with the proapoptotic protein Par-4. Endogenous Par-4 colocalizes with ectopic THAP1 within PML NBs in primary endothelial cells and fibroblasts. The THAP domain is not required for Par-4 binding or PML NB localization but is essential for THAP1 proapoptotic activity. THAP1 potentiates serum withdrawal- and TNF-alpha-induced apoptosis. Co-localization (immunofluorescence), domain deletion analysis, apoptosis assays Oncogene Medium 12717420
2006 THAP1 regulates endothelial cell proliferation and G1/S cell-cycle progression through coordinated repression of pRB/E2F cell-cycle target genes. Chromatin immunoprecipitation showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site in the RRM1 promoter, identifying RRM1 as a direct transcriptional target. Both overexpression and RNAi silencing of THAP1 inhibited EC proliferation and downregulated pRB/E2F target genes including RRM1. Retroviral gene transfer, microarray expression profiling, RNA interference, chromatin immunoprecipitation (ChIP) Blood High 17003378
2007 NMR structure-function analysis of the THAP zinc finger of THAP1 revealed it is an atypical zinc finger of ~80 residues with a short antiparallel beta-sheet interspersed by a loop-helix-loop insertion. Alanine scanning mutagenesis identified critical residues in the loop-helix-loop motif for DNA recognition. NMR chemical shift perturbation mapped the DNA-binding interface to a positively charged area harboring multiple lysine and arginine residues. Multidimensional NMR spectroscopy, deletion mutagenesis, alanine scanning mutagenesis, NMR chemical shift perturbation The Journal of biological chemistry High 18073205
2009 A missense mutation in the THAP1 DNA-binding domain impairs DNA binding, as demonstrated by functional assay, establishing that transcriptional dysregulation via loss of THAP1 DNA-binding activity underlies DYT6 dystonia. Functional DNA-binding assay (electromobility shift or equivalent), mutation analysis Nature genetics Medium 19182804
2010 THAP1 associates with the transcriptional coactivator HCF-1 and O-GlcNAc transferase (OGT) in vivo. THAP1 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM). ChIP assays showed that endogenous THAP1 mediates recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation, and HCF-1 is required for transcriptional activation of RRM1. Proteomic analysis (mass spectrometry), in vitro binding assays, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNA interference The Journal of biological chemistry High 20200153
2010 THAP1 binds directly to the core promoter of TOR1A (DYT1) and represses its expression. Dystonia-associated mutant THAP1 shows decreased repression of TOR1A, as demonstrated by electromobility shift assays and ChIP-qPCR. Pathophysiologic mutations abolish the physical interaction between THAP1 and the TOR1A promoter. Electromobility shift assay (EMSA), chromatin immunoprecipitation (ChIP)-qPCR, luciferase reporter assays Annals of neurology High 20865765 20976771
2011 THAP1 forms homodimers via its C-terminal coiled-coil domain. The interaction requires residues within a 13-amino-acid region (aa 154–166) containing leucine zipper-like elements. The DYT6 frameshift mutation Q154fs180X, which eliminates most of the coiled-coil domain, abolishes self-association, whereas other tested DYT6 mutations do not prevent dimerization. Co-immunoprecipitation, yeast two-hybrid (implied by domain mapping), deletion and truncation analysis Journal of neurochemistry Medium 21752024
2011 A truncating THAP1 mutation (Asp191Thrfs*9) disrupts nuclear import, altering subcellular localization from nucleus to cytoplasm as shown by immunofluorescence microscopy of transfected cells. Immunofluorescence microscopy of transfected cells, luciferase reporter assay European journal of human genetics Low 21847143
2012 NMR, fluorescence, DSF, and ITC analyses of DYT6 missense mutations in the THAP domain showed that none completely abolish DNA binding; some mutations even bind DNA more strongly than wild-type. However, several mutations decrease protein thermostability, with unfolding temperatures dropping from 46°C (wild-type) to below 37°C for mutations affecting zinc coordination, the hydrophobic core, or the C-terminal AVPTIF motif, suggesting that reduced population of folded protein under physiological conditions may account for disease. NMR spectroscopy, fluorescence spectroscopy, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC) Nucleic acids research High 22844099
2012 Truncated THAP1 mutations (F22fs71X and F25fs53X) alter subcellular localization to both cytoplasm and nucleus, whereas missense mutations (C54F and L180S) remain predominantly nuclear, as shown by immunofluorescence and Western blot in transfected HEK-293T cells. Immunofluorescence microscopy, Western blot, transfection in HEK-293T cells Parkinsonism & related disorders Low 22652465
2014 THAP1 autoregulates its own expression by binding to the THAP1 minimal promoter (a 480-bp fragment) and repressing transcription. This was demonstrated by luciferase reporter assays and quantitative ChIP. DYT6-causing mutations disrupt this autoregulation. Overexpressed THAP1 is preferentially degraded via the proteasome, and endogenous THAP1 levels are reduced in cells overexpressing wild-type THAP1. Luciferase reporter assay, quantitative ChIP, RT-qPCR, proteasome inhibitor treatment Biochimica et biophysica acta Medium 25088175
2014 Endogenous THAP1 exists as multiple protein species (29–30 kDa, 32 kDa, 47 kDa, and 50–52 kDa) in neurons. The 50-kDa species is exclusively detected in murine brain and testes and is localized to the nuclear compartment, distinct from non-neuronal isoforms, suggesting neuron-specific post-translational modifications. Western blotting, immunoprecipitation, DNA oligonucleotide affinity chromatography, subcellular fractionation Acta neuropathologica communications Medium 25231164
2017 THAP1 is essential for timing the initiation of CNS myelination in a cell-autonomous manner within the oligodendrocyte (OL) lineage. Conditional deletion of THAP1 in the CNS retards OL maturation, delays myelination, and causes persistent motor deficits. Loss of THAP1 disrupts a core set of OL maturation genes and reduces DNA occupancy of YY1, a transcription factor required for OL maturation. Conditional knockout mouse (CNS-specific Cre), OL progenitor purification and developmental assays, ChIP, motor behavior testing Developmental cell High 28697333
2017 THAP1 regulates embryonic stem cell survival, proliferation, and neuroectodermal differentiation. Loss of THAP1 or expression of a disease-causing mutation enhances cell death, prolongs pluripotency gene expression (Nanog, Prdm14, Rex1) upon differentiation, and impairs upregulation of ectodermal genes. ChIP-Seq reveals that these activities are partly due to indirect regulation of gene expression. Knockout ESCs, disease-mutation knock-in ESCs, ChIP-Seq, differentiation assays, cell survival assays Stem cell reports Medium 28579396
2017 The THAP1 homodimerization domain maps to amino acids 139–185 of the coiled-coil region. Yeast two-hybrid, GST pull-down, and cross-linking assays confirmed this region mediates homodimerization. Nine DYT6-causing missense mutations within this region had no effect on THAP1 dimerization. Yeast two-hybrid, GST pull-down, formaldehyde cross-linking assays Journal of molecular neuroscience Medium 28299530
2018 Heterozygous Thap1 C54Y or ΔExon2 alleles in mouse striatum and cerebellum dysregulate pathways including eIF2α signaling, mitochondrial dysfunction, neuron projection development, axonal guidance signaling, and synaptic long-term depression in a genotype- and tissue-dependent manner. There is a unique neuronal 50-kDa Thap1 immunoreactive species, and Thap1 levels are auto-regulated at the mRNA level. Electrophysiological and neurite outgrowth deficits consistent with pathway enrichments were partially corrected by salubrinal. RNA-Seq (in vivo), electrophysiology, neurite outgrowth assays, pharmacological rescue PLoS genetics Medium 29364887
2021 THAP1, together with YY1 and HCF1, binds directly to the SHLD1 promoter and cooperatively maintains low basal expression of the Shieldin component SHLD1, thereby regulating the choice between end protection and resection during DNA double-strand break repair. Loss of THAP1-dependent SHLD1 expression confers cross-resistance to PARP inhibitors and cisplatin in BRCA1-deficient cells. ChIP, promoter reporter assays, PARP inhibitor sensitivity assays, genetic rescue experiments in BRCA1-deficient cells Molecular cell High 33857404
2021 THAP1 modulates oligodendrocyte maturation by regulating lysosomal glycosaminoglycan (GAG) catabolism in OPCs. Thap1-null OPCs accumulate and secrete excess GAGs, inhibiting their maturation via an autoinhibitory mechanism. THAP1 binds to and regulates the GusB gene encoding β-glucuronidase. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1-null OL maturation deficits in vitro and in vivo. Thap1 knockout OPCs, ChIP (GusB promoter binding), glycosaminoglycan quantification, rescue by GAG-degrading enzymes and GusB overexpression in vitro and in vivo Proceedings of the National Academy of Sciences of the United States of America High 34312226
2021 Dystonia-specific THAP1 mutations dysregulate genes related to neurodevelopment, lysosomal lipid metabolism, and myelin in near-isogenic iPSC-derived neural stem cells. In vivo, Thap1-disruptive alleles in mice cause significant changes in myelin gene expression and reduction of myelin structural integrity. iPSC-derived neural stem cells (allelic series of 8 mutations), RNA-Seq, mouse myelin histology/gene expression American journal of human genetics High 34672987
2022 The DYT6 missense mutation F81L (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. THAP1F81L exhibits normal DNA binding but causes significantly reduced DNA binding of its transcriptional partner YY1 at target promoters, suggesting the mutation disrupts formation of an active transcription complex rather than direct DNA binding. Knock-in mouse model, ChIP (YY1 and THAP1 occupancy), myelination assays, transcriptional reporter assays Human molecular genetics High 34686877
2022 THAP1 regulates gene expression mainly through control of SP1 family members SP1 and SP4 in a cell-type-dependent manner. ChIP-seq showed THAP1 directly targets only a minority of differentially expressed genes; the majority are regulated indirectly via SP1/SP4. Common dysregulated genes across THAP1 patient neurons and knockout rat striatum involve synaptic transmission, nervous system development, and locomotor behavior pathways. ChIP-seq, RNA-seq, transcriptomic comparison across multiple model systems (patient iPSC-derived neurons, KO rat striatum, patient frontal cortex), electrophysiology, behavioral assays Brain High 35015830
2013 Par-4 and THAP1 form a protein complex via interaction of their carboxyl termini, and this complex binds to the CCAR1 promoter through the zinc-dependent DNA-binding domain of THAP1 at its amino terminus. The Par-4/THAP1 complex and Notch3 competitively bind to the CCAR1 promoter and antagonistically regulate alternative pre-mRNA splicing of CCAR1 via splicing factors SRp40 and SRp55, determining T-ALL cell survival. Co-immunoprecipitation, luciferase reporter assay, ChIP, alternative splicing analysis Oncogene Medium 23975424
2020 THAP1 directly binds the promoter of the SOD2 (superoxide dismutase 2) gene as shown by ChIP-seq, and overexpression of THAP1 in SK-N-AS cells increases SOD2 protein expression, whereas fibroblasts from THAP1 patients show reduced SOD2 expression. Disease mutations C54Y and F81L decrease THAP1 protein stability. ChIP-seq, microarray expression profiling, Western blot, patient fibroblast analysis Journal of molecular neuroscience Medium 32112337
2025 THAP1 directly regulates the expression of PSMB5, which encodes the central protease subunit β5 of the 26S proteasome. Depletion of THAP1 disrupts proteasome assembly, reduces proteasome activity, and leads to accumulation of ubiquitinated proteins and cell death. This was identified through a genome-wide genetic screen and confirmed by direct PSMB5 promoter binding and rescue experiments. Genome-wide genetic screen (DepMap coessentiality), THAP1 depletion, proteasome activity assays, ubiquitinated protein accumulation assay, PSMB5 promoter binding assays, RNA-seq, deep mutational scanning of THAP1 Nature communications High 39929834 39952963
2026 THAP1 functions as a maternal effect factor in mouse oocytes and early embryos. Oocyte-specific deletion of Thap1 causes 1-2-cell arrest, defective zygotic genome activation, and impaired female fertility. Mechanistically, THAP1 activates Rrm1 (ribonucleotide reductase) in oocytes to generate dNTPs; overexpression of Rrm1 in Thap1 maternal-KO zygotes nearly fully rescues 2-cell progression and ZGA. Oocyte-specific conditional knockout, low-input metabolomics, RNA-seq (ZGA assay), Rrm1 mRNA rescue by overexpression EMBO reports High 41731150
2021 Loss of THAP1 in striatal medium spiny neurons derived from DYT-THAP1 patient iPSCs results in significantly lower GABA-evoked calcium amplitudes and marked downregulation of the GABA-A receptor alpha2 subunit gene, lower frequency of miniature postsynaptic currents, and elevated spontaneous action potential frequency, indicating decreased GABAergic transmission and neuronal disinhibition/hyperexcitability. iPSC-derived medium spiny neurons, calcium imaging, qPCR, whole-cell patch-clamp electrophysiology Frontiers in cell and developmental biology Medium 34095114
2019 Conditional deletion of Thap1 in neural/glial precursors (nestin-Cre) causes pronounced locomotor deficits with transcriptional changes in genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis, and dopamine signaling. Germline deletion of Thap1 is embryonic lethal. Heterozygous mice show autoregulation of Thap1 mRNA with compensatory upregulation from the intact allele. Conditional knockout mice (nestin-Cre), germline knockout, RNA-seq, behavioral testing Human molecular genetics Medium 30590536

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nature genetics 244 19182804
2009 Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. The Lancet. Neurology 130 19345147
2005 The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity. Proceedings of the National Academy of Sciences of the United States of America 126 15863623
2003 THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Oncogene 124 12717420
2006 The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes. Blood 117 17003378
2009 Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. The Lancet. Neurology 116 19345148
2010 The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. The Journal of biological chemistry 91 20200153
2010 Novel THAP1 sequence variants in primary dystonia. Neurology 83 20083799
2010 THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 82 20211909
2010 DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Movement disorders : official journal of the Movement Disorder Society 76 20687191
2010 The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Annals of neurology 75 20976771
2012 Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism & related disorders 72 22377579
2007 Structure-function analysis of the THAP zinc finger of THAP1, a large C2CH DNA-binding module linked to Rb/E2F pathways. The Journal of biological chemistry 68 18073205
2011 Pallidal deep brain stimulation for DYT6 dystonia. Journal of neurology, neurosurgery, and psychiatry 66 21949105
2010 Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Annals of neurology 66 20865765
2018 Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLoS genetics 63 29364887
2013 SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 60 24135862
2007 Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. American journal of medical genetics. Part A 54 17702011
2012 THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. Movement disorders : official journal of the Movement Disorder Society 53 22903657
2011 DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Human mutation 50 21793105
2017 The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage. Developmental cell 49 28697333
2015 Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. Human molecular genetics 47 26376866
2011 Identification and functional analysis of novel THAP1 mutations. European journal of human genetics : EJHG 42 21847143
2009 Mutation screening of the DYT6/THAP1 gene in Italy. Movement disorders : official journal of the Movement Disorder Society 37 19908325
2010 Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Movement disorders : official journal of the Movement Disorder Society 35 20687193
2011 Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Movement disorders : official journal of the Movement Disorder Society 33 21425335
2017 THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation. Stem cell reports 32 28579396
2013 Par-4/THAP1 complex and Notch3 competitively regulated pre-mRNA splicing of CCAR1 and affected inversely the survival of T-cell acute lymphoblastic leukemia cells. Oncogene 31 23975424
2019 Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes. Human molecular genetics 30 30590536
2015 Long-term effect on dystonia after pallidal deep brain stimulation (DBS) in three members of a family with a THAP1 mutation. Journal of neurology 30 26486352
2014 Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Movement disorders : official journal of the Movement Disorder Society 30 24500857
2010 Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China. European journal of neurology 30 20825472
2014 Deep brain stimulation of the thalamic ventral lateral anterior nucleus for DYT6 dystonia. Stereotactic and functional neurosurgery 29 25359437
2010 Prevalence of THAP1 sequence variants in German patients with primary dystonia. Movement disorders : official journal of the Movement Disorder Society 29 20669277
2011 Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain. Journal of neurochemistry 26 21752024
2021 The dystonia gene THAP1 controls DNA double-strand break repair choice. Molecular cell 24 33857404
2021 Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin. American journal of human genetics 21 34672987
2012 Towards the classification of DYT6 dystonia mutants in the DNA-binding domain of THAP1. Nucleic acids research 21 22844099
2012 Neural expression of the transcription factor THAP1 during development in rat. Neuroscience 21 23219941
2014 THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression. Biochimica et biophysica acta 20 25088175
2019 The Effect of Globus Pallidus Interna Deep Brain Stimulation on a Dystonia Patient with the GNAL Mutation Compared to Patients with DYT1 and DYT6. Journal of movement disorders 18 31158945
2015 DYT6 Dystonia: A Neuropathological Study. Neuro-degenerative diseases 18 26610312
2014 Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia. Movement disorders : official journal of the Movement Disorder Society 18 24862462
2011 The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia. Movement disorders : official journal of the Movement Disorder Society 18 21370264
2010 Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion. Movement disorders : official journal of the Movement Disorder Society 18 20925076
2014 A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia. Molecular genetics & genomic medicine 17 24936516
2011 THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression. Journal of neurology 17 21800139
2012 Subcellular distribution of THAP1 and alterations in the microstructure of brain white matter in DYT6 dystonia. Parkinsonism & related disorders 16 22652465
2021 Linking Penetrance and Transcription in DYT-THAP1: Insights From a Human iPSC-Derived Cortical Model. Movement disorders : official journal of the Movement Disorder Society 15 33547842
2021 THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes. Proceedings of the National Academy of Sciences of the United States of America 15 34312226
2020 Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia. Journal of molecular neuroscience : MN 15 32112337
2012 Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia. Journal of neurology 13 23180184
2022 A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding. Human molecular genetics 12 34686877
2021 Reduced Expression of GABA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons. Frontiers in cell and developmental biology 12 34095114
2016 Genetic screening of THAP1 in primary dystonia patients of India. Neuroscience letters 12 27913194
2019 Intracranial calcifications and dystonia associated with a novel deletion of chromosome 8p11.2 encompassing SLC20A2 and THAP1. BMJ case reports 11 31133547
2022 DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family. Brain : a journal of neurology 10 35015830
2017 In-depth Characterization of the Homodimerization Domain of the Transcription Factor THAP1 and Dystonia-Causing Mutations Therein. Journal of molecular neuroscience : MN 10 28299530
2014 Novel THAP1 variants in Brazilian patients with idiopathic isolated dystonia. Journal of the neurological sciences 10 24976531
2014 Dystonia type 6 gene product Thap1: identification of a 50 kDa DNA-binding species in neuronal nuclear fractions. Acta neuropathologica communications 10 25231164
2011 Novel THAP1 gene mutations in patients with primary dystonia from southwest China. Journal of the neurological sciences 10 21839475
2014 High variability of clinical symptoms in a Polish family with a novel THAP1 mutation. The International journal of neuroscience 8 25385508
2025 The DYT6 dystonia causative protein THAP1 is responsible for proteasome activity via PSMB5 transcriptional regulation. Nature communications 7 39952963
2014 DYT6 in Brazil: Genetic Assessment and Clinical Characteristics of Patients. Tremor and other hyperkinetic movements (New York, N.Y.) 7 24757586
2025 Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression. Nature communications 6 39929834
2012 Spatial Discrimination Threshold Abnormalities are not Detected in a Pilot Study of DYT6 Dystonia Mutation Carriers. Tremor and other hyperkinetic movements (New York, N.Y.) 6 23439738
2018 Generation and characterization of eight human-derived iPSC lines from affected and unaffected THAP1 mutation carriers. Stem cell research 4 30316041
2024 Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/- mice. Neurobiology of disease 3 39732371
2022 A case of novel DYT6 dystonia variant with serious complications after deep brain stimulation therapy: a case report. BMC neurology 3 36096774
2022 Emerging role of a systems biology approach to elucidate factors of reduced penetrance: transcriptional changes in THAP1-linked dystonia as an example. Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V 3 38835919
2020 Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review. European journal of neurology 3 33175450
2019 Cerebellar Involvement in DYT-THAP1 Dystonia. Cerebellum (London, England) 3 31367947
2024 MS4A3 Promotes the Chemosensitivity of Lung Cancer via THAP1/EGFR Pathways. Critical reviews in eukaryotic gene expression 2 39180203
2021 Pharmacological perturbation reveals deficits in D2 receptor responses in Thap1 null mice. Annals of clinical and translational neurology 2 34802187
2016 Lack of association between TOR1A and THAP1 mutations and sporadic adult-onset primary focal dystonia in a Chinese population. Clinical neurology and neurosurgery 2 26803725
2016 New THAP1 mutation and role of putative modifier in TOR1A. Acta neurologica Scandinavica 2 26940431
2015 Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions. PloS one 2 26087139
2024 Case report: Lingual dystonia symptoms treated with botulinum toxin in patients with THAP1 mutation. Dystonia (Lausanne, Switzerland) 1 40735195
2023 Generalized Dystonia Due to a Pathogenic THAP1 Variant Showing Sustained Response to Globus Pallidus Deep Brain Stimulation. Tremor and other hyperkinetic movements (New York, N.Y.) 1 37637848
2023 Transcriptional regulatory network for neuron-glia interactions and its implication for DYT6 dystonia. Dystonia (Lausanne, Switzerland) 1 38737544
2022 Changes in pallidal neural activity following long-term symptom improvement from botulinum toxin treatment in DYT6 dystonia: a case report. Journal of medical case reports 1 34998426
2014 Intrafamilial variability of the primary dystonia DYT6 phenotype caused by p.Cys5Trp mutation in THAP1 gene. Neurologia i neurochirurgia polska 1 25168324
2026 THAP1 is a maternal effect factor required for the first cell cycle via Rrm1 in early mouse embryos. EMBO reports 0 41731150

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