Affinage

DNTTIP1

Deoxynucleotidyltransferase terminal-interacting protein 1 · UniProt Q9H147

Length
329 aa
Mass
37.0 kDa
Annotated
2026-04-28
24 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNTTIP1 is a dimeric chromatin-binding scaffold protein that nucleates the MiDAC histone deacetylase complex, linking HDAC1/2 catalytic activity to specific genomic loci to regulate gene silencing, cell-cycle progression, mitosis, and embryonic development. Its N-terminal dimerization domain assembles the MIDEAS–HDAC1 complex while its C-terminal SKI/SNO/DAC domain binds nucleosomes and AT-tract–flanked palindromic DNA sequences (5′-TGCATG-3′), directing HDAC1/2-mediated H3K27 deacetylation at target promoters including BMF, DUSP2, and E-cadherin (PMID:25653165, PMID:35689852, PMID:41603084). Loss of DNTTIP1 in mice causes late-embryonic lethality with cardiac and hematopoietic defects, and in cancer cells leads to chromosome misalignment, cell-cycle arrest, and apoptosis (PMID:32591534, PMID:29855544, PMID:41603084). Independently of its MiDAC role, DNTTIP1 directly binds terminal deoxynucleotidyltransferase (TdT), modulating its activity and facilitating CUL3-dependent TdT ubiquitylation during V(D)J recombination (PMID:11473582, PMID:19930467).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Identifying DNTTIP1 as a direct TdT-interacting protein established that TdT activity in thymocytes is regulated by a dedicated nuclear partner rather than acting autonomously.

    Evidence Yeast two-hybrid, in vitro binding, gel filtration, and TdT activity assays in thymocyte nuclear extracts

    PMID:11473582

    Open questions at the time
    • Physiological relevance of TdT enhancement in vivo during V(D)J recombination not tested
    • No structural information on the TdT–DNTTIP1 interface
  2. 2006 High

    Discovery that DNTTIP1 connects to the TReP-132 (TRERF1) regulatory network revealed a multi-protein control circuit governing TdT activity, where TRERF1 suppresses TdT while DNTTIP1 activates it.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, in vitro TdT assay, co-localization in COS7 cells

    PMID:16371131

    Open questions at the time
    • Stoichiometry and competition between DNTTIP1 and TRERF1 for TdT not resolved
    • In vivo functional consequence in lymphocyte development unknown
  3. 2007 High

    Mapping of DNTTIP1's modular architecture — TdT-binding, DNA-binding (AT-hook and HTH), dimerization, and NLS domains — explained how a single protein coordinates TdT regulation with sequence-specific DNA recognition.

    Evidence Deletion mutagenesis and in vitro DNA-binding and TdT activity assays

    PMID:17663723

    Open questions at the time
    • No crystal structure of the DNA-binding domains at this point
    • Genome-wide binding targets unknown
  4. 2009 Medium

    Demonstration that DNTTIP1 recruits the CUL3 adaptor BPOZ-2 to facilitate TdT ubiquitylation revealed a role in targeting TdT for proteasomal degradation, adding post-translational control to V(D)J recombination.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, ubiquitylation assay in 293T cells

    PMID:19930467

    Open questions at the time
    • Ubiquitylation of endogenous TdT in primary thymocytes not shown
    • Whether DNTTIP1-mediated TdT degradation affects V(D)J diversity in vivo untested
  5. 2013 Medium

    SELEX and ChIP identification of the consensus DNA motif (AT-tract flanking 5′-GNTGCATG-3′) and demonstration that DNTTIP1 activates RAB20 transcription established it as a sequence-specific transcriptional regulator beyond its TdT role.

    Evidence SELEX, mutagenesis, ChIP, luciferase reporter, siRNA knockdown with RT-qPCR

    PMID:23874396

    Open questions at the time
    • Mechanism of transcriptional activation unclear — co-activator recruitment not identified
    • Genome-wide target repertoire incomplete
  6. 2015 High

    Crystal and NMR structures revealed the N-terminal dimerization domain (novel fold) and C-terminal SKI/SNO/DAC domain that binds nucleosomes, establishing DNTTIP1 as the architectural scaffold of the MiDAC (MIDEAS–HDAC1) deacetylase complex and redefining its primary cellular function as chromatin regulation.

    Evidence X-ray crystallography, NMR, nucleosome-binding assays, co-IP, domain mutagenesis; genome-wide ChIP-seq with reporter validation

    PMID:25619743 PMID:25653165

    Open questions at the time
    • How dimerization-driven assembly positions four HDAC copies was not yet resolved
    • Functional targets of MiDAC-mediated deacetylation not identified
  7. 2018 Medium

    Knockdown studies in oral squamous cell carcinoma linked the DNTTIP1–HDAC axis to p53 deacetylation and cell-cycle control, providing the first cancer-relevant phenotype and connecting MiDAC to G1/S checkpoint regulation.

    Evidence siRNA knockdown, cell-cycle analysis, western blotting for acetyl-p53 and p21, xenograft model

    PMID:29855544

    Open questions at the time
    • Whether p53 is a direct MiDAC substrate or an indirect effect not distinguished
    • Single cancer type studied
  8. 2020 High

    CryoEM of the full MiDAC complex revealed four outward-facing HDAC1 active sites scaffolded by DNTTIP1/MIDEAS, and DNTTIP1-null mice died in late embryogenesis with heart and hematopoietic defects, definitively establishing MiDAC as essential for mammalian development and multi-nucleosome deacetylation.

    Evidence CryoEM structure, DNTTIP1 and MIDEAS knockout mice, siRNA with mitotic phenotype quantification

    PMID:32591534

    Open questions at the time
    • Direct genomic targets responsible for cardiac and hematopoietic failure not identified
    • Processive multi-nucleosome deacetylation model not functionally tested
  9. 2021 Medium

    Identification of LSD1 as a DNTTIP1 interactor recruited to the E-cadherin promoter expanded MiDAC's chromatin-modifying repertoire to include histone demethylation and linked it to epithelial-mesenchymal transition.

    Evidence Co-IP, ChIP, siRNA, migration/invasion assays, xenograft in lung cancer cells

    PMID:35008676

    Open questions at the time
    • Whether LSD1 interaction is MiDAC-dependent or independent not determined
    • Single cancer context
  10. 2022 High

    ChIP and transcriptomic studies showed DNTTIP1 recruits HDAC1 to maintain H3K27 deacetylation at the DUSP2 promoter, silencing DUSP2 to sustain ERK signaling and metastasis, and separately, DNTTIP1 participates in a ZFP541-containing spermatocyte complex required for meiotic pachytene progression, revealing tissue-specific complex diversity.

    Evidence ChIP, co-IP, reporter assay, RNA-seq, functional assays in NPC cells; co-IP and KO mouse model in spermatocytes

    PMID:35341968 PMID:35689852

    Open questions at the time
    • Whether spermatocyte complex is distinct from canonical MiDAC not resolved
    • DNTTIP1-specific contribution versus ZFP541 contribution in meiosis unclear
  11. 2025 High

    A gain-of-function MIDEAS variant (p.Tyr654Ser) displacing the auto-inhibitory loop from the HDAC active site demonstrated that the DNTTIP1/MIDEAS scaffold directly controls HDAC catalytic output, and that dysregulated MiDAC activity causes a neurodevelopmental syndrome.

    Evidence CryoEM structure with mutant, patient fibroblast gene expression, biochemical deacetylase assays

    PMID:41290615

    Open questions at the time
    • Whether DNTTIP1 variants independently cause disease not tested
    • Brain-specific MiDAC targets not identified
  12. 2026 High

    Multi-omic profiling in acute leukemia established BMF as a direct MiDAC target silenced via H3K27 deacetylation; DNTTIP1 depletion derepresses BMF and triggers coordinated apoptosis and autophagy, providing a therapeutic vulnerability in leukemia.

    Evidence ChIP-qPCR, CUT&Tag, ATAC-seq, RNA-seq, genetic depletion, in vivo leukemia models, drug synergy assays

    PMID:41603084

    Open questions at the time
    • Whether BMF silencing is universal across leukemia subtypes not established
    • Contribution of individual HDAC1 versus HDAC2 copies within MiDAC not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how DNTTIP1's TdT-regulatory and MiDAC-scaffolding functions are coordinated in lymphocytes; the complete catalog of direct MiDAC genomic targets across tissues; and whether DNTTIP1 germline variants cause human Mendelian disease.
  • No integration of TdT and MiDAC functions in a single experimental system
  • Tissue-specific MiDAC target landscapes remain incomplete
  • No human DNTTIP1 disease mutations reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BPOZ2DNTTHDAC1LSD1MIDEASTRERF1ZFP541
Complex memberships
MiDAC (MIDEAS-DNTTIP1-HDAC1/2)ZFP541-DNTTIP1-HDAC1/2 spermatocyte complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 DNTTIP1 (TdIF1) directly binds to terminal deoxynucleotidyltransferase (TdT) and enhances TdT activity up to fourfold in vitro; both proteins co-exist in a ~232 kDa nuclear complex in thymocytes. Yeast two-hybrid, in vitro binding, gel filtration, in vitro TdT activity assay Genes to cells High 11473582
2006 DNTTIP1 (TdIF1) interacts with TReP-132 (TRERF1), which in turn directly binds TdT through its N-terminal region and reduces TdT activity to ~2.5% of maximum in vitro; TdIF1 and TReP-132 co-localize in the nucleus. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, in vitro TdT activity assay, co-localization in COS7 cells Genes to cells High 16371131
2007 DNTTIP1 (TdIF1) contains distinct TdT-binding, DNA-binding, dimerization, and nuclear localization signal (NLS) regions; it binds dsDNA via three regions (residues 1-75, an AT-hook-like motif, and a predicted helix-turn-helix motif), preferentially at AT-rich sequences, and blocks TdT access to DNA ends; in the presence of dsDNA, TdIF1 releases TdT to allow activity. Deletion mutagenesis, in vitro DNA-binding assays, in vitro TdT activity assay Genes to cells High 17663723
2009 DNTTIP1 (TdIF1) binds BPOZ-2 (an adaptor for E3 ligase CUL3), recruits it from the cytoplasm into the nucleus, and this recruitment facilitates ubiquitylation of TdT. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, co-localization imaging in COS7 and 293T cells, ubiquitylation assay Genes to cells Medium 19930467
2013 DNTTIP1 (TdIF1) recognizes the specific DNA sequence 5'-GNTGCATG-3' following an AT-tract via its Helix-Turn-Helix and AT-hook motifs; it associates with the RAB20 promoter in vivo and upregulates RAB20 transcription. Mutagenesis, SELEX, luciferase reporter assay, ChIP, siRNA knockdown with RT-qPCR PloS one Medium 23874396
2015 DNTTIP1 contains an N-terminal dimerization domain with a novel fold that mediates assembly of the HDAC1:MIDEAS complex, and a C-terminal SKI/SNO/DAC-related domain that binds DNA and nucleosomes; DNTTIP1 therefore acts as a dimeric chromatin-binding module in the MiDAC complex. X-ray crystallography, NMR, in vitro nucleosome-binding assays, co-immunoprecipitation, domain mutagenesis Nucleic acids research High 25653165
2015 In vivo ChIP-seq defines TdIF1 consensus binding as a 160-bp cassette containing AT-tract~palindrome (5'-TGCATG-3')~AT-tract; TdIF1 upregulates transcription of promoters containing this motif, including genes involved in ossification. ChIP-seq, luciferase reporter assay, RT-qPCR Genes to cells Medium 25619743
2020 CryoEM structure of the MiDAC complex reveals four copies of HDAC1 at the periphery with outward-facing active sites, suggesting multi-nucleosome targeting and processive deacetylase activity; DNTTIP1 and MIDEAS form the scaffold. Mice lacking DNTTIP1 die during late embryogenesis with heart malformation and haematopoietic failure, and DNTTIP1 loss causes chromosome alignment defects during mitosis in cancer cell lines. CryoEM structure determination, DNTTIP1 and MIDEAS knockout mice, siRNA knockdown with mitosis phenotype quantification Nature communications High 32591534
2018 DNTTIP1 knockdown in oral squamous cell carcinoma cells causes G1 cell-cycle arrest with increased p53 acetylation and upregulation of p21Cip1, indicating that the DNTTIP1-HDAC complex promotes cell proliferation through deacetylation of p53. siRNA knockdown, cell-cycle analysis, western blotting (acetyl-p53, p21), xenograft model Laboratory investigation Medium 29855544
2021 DNTTIP1 (TdIF1) interacts with LSD1 and recruits it to the E-cadherin promoter, leading to histone demethylation, repression of E-cadherin, and promotion of epithelial-mesenchymal transition in lung cancer cells. Co-immunoprecipitation, ChIP assay, siRNA knockdown, migration/invasion assays, xenograft model International journal of molecular sciences Medium 35008676
2022 DNTTIP1 recruits HDAC1 to the DUSP2 promoter, maintaining deacetylation of histone H3K27 and suppressing DUSP2 expression, which results in ERK pathway activation and elevated MMP2 levels promoting nasopharyngeal carcinoma metastasis. ChIP assay, co-immunoprecipitation, luciferase reporter assay, RNA-seq, western blotting, in vitro and in vivo functional assays EBioMedicine High 35689852
2022 DNTTIP1 interacts with HDAC1/2 and ZFP541 in a spermatocyte complex; ZFP541 binds and activates meiotic gene expression, and DNTTIP1 is a component of this complex required for pachytene progression. Co-immunoprecipitation, genetic knockout mouse model, immunofluorescence Journal of genetics and genomics Medium 35341968
2025 A cryoEM structure of MiDAC shows that the MIDEAS auto-inhibitory loop covers the HDAC active site; a de novo p.Tyr654Ser MIDEAS variant displaces this loop, elevating MiDAC deacetylase activity and causing a multisystem neurodevelopmental syndrome, confirming that DNTTIP1/MIDEAS scaffold assembly controls HDAC catalytic output. CryoEM structure, patient-derived fibroblast gene expression, biochemical deacetylase activity assays Nature communications High 41290615
2026 DNTTIP1 acts as a scaffold within the MiDAC complex recruiting HDAC1/2 to the BMF promoter to maintain H3K27 deacetylation and silence BMF; DNTTIP1 depletion causes H3K27 hyperacetylation at the BMF promoter, BMF upregulation, BCL2 pathway disruption, and coordinated autophagy and apoptosis in acute leukaemia cells. ChIP-qPCR, CUT&Tag, ATAC-seq, RNA-seq, siRNA/genetic depletion, in vivo leukaemia mouse models, drug synergy assays Clinical and translational medicine High 41603084

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure. Nature communications 58 32591534
2015 Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting. Nucleic acids research 53 25653165
2015 The extended AT-hook is a novel RNA binding motif. RNA biology 41 26156556
2022 DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway. EBioMedicine 31 35689852
2001 Terminal deoxynucleotidyltransferase directly interacts with a novel nuclear protein that is homologous to p65. Genes to cells : devoted to molecular & cellular mechanisms 28 11473582
2018 Identification of genes directly responding to DLK1 signaling in Callipyge sheep. BMC genomics 17 29690867
2018 Critical role of deoxynucleotidyl transferase terminal interacting protein 1 in oral cancer. Laboratory investigation; a journal of technical methods and pathology 17 29855544
2021 TdIF1-LSD1 Axis Regulates Epithelial-Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer. International journal of molecular sciences 16 35008676
2007 Identification of functional domains in TdIF1 and its inhibitory mechanism for TdT activity. Genes to cells : devoted to molecular & cellular mechanisms 16 17663723
2018 TdIF1: a putative oncogene in NSCLC tumor progression. Signal transduction and targeted therapy 13 30345081
2022 DNTTIP2 Expression is Associated with Macrophage Infiltration and Malignant Characteristics in Low-Grade Glioma. Pharmacogenomics and personalized medicine 12 35370417
2006 Direct binding of TReP-132 with TdT results in reduction of TdT activity. Genes to cells : devoted to molecular & cellular mechanisms 12 16371131
2020 Searching for a signature involving 10 genes to predict the survival of patients with acute myelocytic leukemia through a combined multi-omics analysis. PeerJ 11 32617195
2022 The ZFP541-KCTD19 complex is essential for pachytene progression by activating meiotic genes during mouse spermatogenesis. Journal of genetics and genomics = Yi chuan xue bao 10 35341968
2015 Definition of the transcription factor TdIF1 consensus-binding sequence through genomewide mapping of its binding sites. Genes to cells : devoted to molecular & cellular mechanisms 7 25619743
2013 TdIF1 recognizes a specific DNA sequence through its Helix-Turn-Helix and AT-hook motifs to regulate gene transcription. PloS one 5 23874396
2009 TdT interacting factor 1 enhances TdT ubiquitylation through recruitment of BPOZ-2 into nucleus from cytoplasm. Genes to cells : devoted to molecular & cellular mechanisms 5 19930467
2022 Identification of HAGHL as a novel metabolic oncogene regulating human colorectal cancer progression. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 4 36417085
2021 A comprehensive analysis of different gene classes in pancreatic cancer: SIGLEC15 may be a promising immunotherapeutic target. Investigational new drugs 4 34515878
2026 DNTTIP1 drives leukaemogenesis through MiDAC-mediated epigenetic silencing of BMF. Clinical and translational medicine 1 41603084
2025 Loss of Elmsan1 in cardiomyocytes leads to age-dependent cardiac dysfunction and reduced lifespan. American journal of physiology. Heart and circulatory physiology 1 40588350
2020 Haplotype Purging After Relaxation of Selection in Lines of Chickens that Had Undergone Long-Term Selection for High and Low Body Weight. Genes 1 32521737
2025 Identification of a novel transcriptome signature for predicting the response to anti-TNF-α treatment in patients with rheumatoid arthritis. Annals of the rheumatic diseases 0 40908203
2025 A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome. Nature communications 0 41290615