Affinage

DNTTIP1

Deoxynucleotidyltransferase terminal-interacting protein 1 · UniProt Q9H147

Length
329 aa
Mass
37.0 kDa
Annotated
2026-06-09
24 papers in source corpus 14 papers cited in narrative 14 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

DNTTIP1 is the DNA/nucleosome-targeting and dimerization subunit of the mitotic deacetylase (MiDAC) complex, a chromatin-modifying machine that silences target genes by histone deacetylation (PMID:25653165, PMID:32591534). Structurally it is bipartite: an N-terminal domain forms a tight homodimer with a novel fold that scaffolds assembly of the HDAC1:MIDEAS complex, while its C-terminal SKI/SNO/DAC-related domain binds DNA and nucleosomes directly (PMID:25653165). Within the assembled MiDAC complex, four peripheral HDAC1 active sites face outward, consistent with processive, multi-nucleosome deacetylation (PMID:32591534). Through this scaffolding role DNTTIP1 recruits HDAC1/2 to specific promoters to maintain deacetylated H3K27 and repress transcription, silencing DUSP2 to activate ERK signaling and drive nasopharyngeal carcinoma metastasis (PMID:35689852) and silencing BMF to sustain BCL2-mediated survival in acute leukaemia (PMID:41603084). DNTTIP1 loss is genetically essential: knockout mice die in late embryogenesis with heart malformation and haematopoietic failure, and depletion disrupts mitotic chromosome alignment in cancer cells (PMID:32591534); the complex also requires DNTTIP1 for pachytene progression during male meiosis via a ZFP541-HDAC1/2 assembly (PMID:35341968). A hyperactivating MIDEAS variant that increases MiDAC deacetylase activity causes a multisystem developmental disorder, underscoring the requirement for tight regulation of DNTTIP1-scaffolded complex output (PMID:41290615). Independently of MiDAC, DNTTIP1 (TdIF1) was first characterized as a sequence-specific and AT-rich DNA-binding protein that binds terminal deoxynucleotidyltransferase (TdT) and modulates its activity (PMID:11473582, PMID:17663723), and it can recruit additional co-regulators including LSD1 and the CUL3 adaptor BPOZ-2 to chromatin (PMID:35008676, PMID:19930467).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 Medium

    Established DNTTIP1's first known function by identifying it as a direct TdT-binding partner that modulates the enzyme and resides in a large nuclear protein complex.

    Evidence Yeast two-hybrid, gel filtration co-elution, and in vitro TdT activity assay in thymocyte lysate

    PMID:11473582

    Open questions at the time
    • No mutagenesis defining the interaction interface
    • Identity of other ~232 kDa complex members not resolved
  2. 2006 Medium

    Defined a regulatory triad showing DNTTIP1 and TReP-132 both bind TdT and co-localize, refining how TdT activity is negatively controlled during recombination.

    Evidence Yeast two-hybrid, GST pull-down, IP, in vitro TdT activity assay, and co-localization microscopy

    PMID:16371131

    Open questions at the time
    • Cellular consequences for V(D)J recombination not directly tested
    • Single-lab interaction data
  3. 2007 High

    Mapped DNTTIP1's DNA-binding architecture and showed dsDNA competes TdT off the complex, mechanistically linking its DNA binding to TdT regulation.

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

    PMID:17663723

    Open questions at the time
    • In vitro only; in vivo relevance to recombination not established
    • Structural basis of DNA selectivity not yet solved at this stage
  4. 2009 Medium

    Showed DNTTIP1 couples TdT to the ubiquitin-proteasome system by recruiting the CUL3 adaptor BPOZ-2 into the nucleus.

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

    PMID:19930467

    Open questions at the time
    • Endogenous TdT turnover via this axis not demonstrated
    • Overexpression-based ubiquitylation readout
  5. 2013 Medium

    Identified a specific DNA recognition sequence for DNTTIP1 and demonstrated it can activate transcription of a target gene, extending its role to sequence-specific gene regulation.

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

    PMID:23874396

    Open questions at the time
    • Mechanism of transcriptional activation not defined
    • Single target gene examined
  6. 2015 Medium

    Generalized DNTTIP1's genomic targeting by defining a composite AT-tract/palindrome cassette driving its transcriptional upregulation of an ossification-related gene set.

    Evidence ChIP-seq, luciferase reporter, and RT-qPCR

    PMID:25619743

    Open questions at the time
    • Co-factors mediating activation at these sites unresolved
    • Relationship to repressive MiDAC function not reconciled
  7. 2015 High

    Reframed DNTTIP1 as a structural subunit of the MiDAC HDAC complex, resolving its bipartite role as both a homodimerization scaffold for HDAC1:MIDEAS and a direct DNA/nucleosome binder.

    Evidence Crystal structures of two DNTTIP1 domains with nucleosome-binding and complex-assembly assays

    PMID:25653165

    Open questions at the time
    • Structure of the intact assembled complex not yet determined
    • Genomic targets of the complex not mapped
  8. 2018 Medium

    Linked DNTTIP1-HDAC activity to proliferation control, showing its loss arrests the cell cycle through p53 hyperacetylation and p21 induction.

    Evidence siRNA knockdown, flow cytometry, immunoblot for acetyl-p53/p21, and xenograft in oral squamous carcinoma

    PMID:29855544

    Open questions at the time
    • Whether p53 is a direct MiDAC substrate not shown
    • MiDAC complex context not directly tested here
  9. 2020 High

    Provided the architecture and physiological necessity of MiDAC, showing four outward-facing HDAC1 active sites and that DNTTIP1 is essential for mitotic chromosome alignment and embryonic heart/haematopoietic development.

    Evidence CryoEM of intact MiDAC, CRISPR/siRNA in cancer cells, and DNTTIP1/MIDEAS knockout mice

    PMID:32591534

    Open questions at the time
    • Direct substrate nucleosomes in cells not enumerated
    • How chromosome alignment is mechanistically controlled by deacetylation unresolved
  10. 2021 Medium

    Showed DNTTIP1 recruits the demethylase LSD1 to a target promoter, expanding its co-regulator repertoire beyond HDACs and linking it to EMT suppression.

    Evidence Co-IP, ChIP, siRNA knockdown, migration/invasion assays, and xenograft in NSCLC

    PMID:35008676

    Open questions at the time
    • Whether LSD1 recruitment is MiDAC-dependent unclear
    • Single target locus
  11. 2022 Medium

    Demonstrated locus-specific gene silencing by DNTTIP1, recruiting HDAC1 to the DUSP2 promoter to maintain H3K27 deacetylation and aberrantly activate ERK signaling in metastasis.

    Evidence ChIP, co-IP, luciferase reporter, RNA-seq, siRNA, xenograft, and HDAC inhibitor treatment

    PMID:35689852

    Open questions at the time
    • Genome-wide scope of DNTTIP1-dependent H3K27 deacetylation not defined here
    • Single cancer context
  12. 2022 Medium

    Extended DNTTIP1's complex membership to a ZFP541-HDAC1/2 assembly required for meiotic pachytene progression in spermatogenesis.

    Evidence Co-IP and genetic knockout with spermatocyte phenotyping in mice

    PMID:35341968

    Open questions at the time
    • Direct DNTTIP1 contribution versus ZFP541 not dissected
    • Target genes governing meiotic arrest not fully defined
  13. 2025 High

    Connected MiDAC dysregulation to human disease, showing a hyperactivating MIDEAS variant displaces an auto-inhibitory loop to increase deacetylase activity and cause a multisystem developmental disorder.

    Evidence CryoEM of variant complex, patient fibroblast transcriptomics, and degron-mediated MiDAC degradation

    PMID:41290615

    Open questions at the time
    • DNTTIP1's specific contribution to the auto-inhibitory regulation not isolated
    • Causal DNTTIP1 variants in patients not reported here
  14. 2026 High

    Showed DNTTIP1 acts as a MiDAC scaffold that silences BMF via H3K27 deacetylation, defining a therapeutically actionable apoptosis/autophagy axis in leukaemia.

    Evidence CUT&Tag, ATAC-seq, RNA-seq, ChIP-qPCR, knockdown, in vivo leukaemia models, and drug synergy assays

    PMID:41603084

    Open questions at the time
    • Whether BMF is a direct versus indirect target not fully separated
    • Generalization beyond leukaemia not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DNTTIP1 reconciles its dual activities — sequence-specific transcriptional activation versus MiDAC-mediated repressive deacetylation — and what governs its choice of genomic targets remain unresolved.
  • No unified model linking AT-tract/palindrome activation sites to repressive MiDAC recruitment
  • Determinants of context-specific co-regulator selection (HDAC1/2, LSD1, BPOZ-2) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2
Partners
BPOZ-2HDAC1HDAC2LSD1MIDEASTDT (DNTT)TREP-132ZFP541
Complex memberships
MiDAC (HDAC1:MIDEAS:DNTTIP1)

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; TdIF1 and TdT co-exist as members of a ~232 kDa protein complex in thymocyte lysate. TdIF1 contains AT-hook (HMG-I/Y) DNA binding domains and can bind single- and double-stranded DNA. Yeast two-hybrid, co-elution by gel filtration, in vitro TdT activity assay Genes to cells : devoted to molecular & cellular mechanisms Medium 11473582
2007 DNTTIP1 (TdIF1) negatively regulates TdT activity by binding the Pol beta-like region of TdT and blocking TdT access to DNA ends. In the presence of dsDNA, TdIF1 preferentially binds dsDNA, releasing active TdT from the TdIF1/TdT complex. Three DNA-binding regions were mapped: residues 1–75, an AT-hook-like motif (ALM), and a predicted helix-turn-helix (HTH) motif; ALM binds AT-rich DNA; a bipartite nuclear localization signal overlaps ALM. Deletion mutagenesis, in vitro TdT activity assays, DNA binding assays Genes to cells : devoted to molecular & cellular mechanisms High 17663723
2006 DNTTIP1 (TdIF1) directly binds TReP-132, and TdT also directly binds TReP-132 through its N-terminal region; TReP-132 reduces TdT activity to 2.5% of maximum in vitro, acting as a negative regulator of TdT during V(D)J recombination. TdIF1, TReP-132, and TdT co-localize in the nucleus. Yeast two-hybrid, GST pull-down, immunoprecipitation, in vitro TdT activity assay, co-localization by fluorescence microscopy Genes to cells : devoted to molecular & cellular mechanisms Medium 16371131
2009 DNTTIP1 (TdIF1) directly binds BPOZ-2 (an adaptor for E3 ligase CUL3) and recruits BPOZ-2 from the cytoplasm into the nucleus; nuclear BPOZ-2 enhances TdT ubiquitylation when co-expressed with TdIF1, indicating DNTTIP1 facilitates TdT proteasomal targeting via CUL3-BPOZ-2. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, co-localization fluorescence microscopy, ubiquitylation assay in 293T cells Genes to cells : devoted to molecular & cellular mechanisms Medium 19930467
2013 DNTTIP1 (TdIF1) recognizes the specific DNA sequence 5'-GNTGCATG-3' following an AT-tract via its HTH and AT-hook motifs, and activates transcription of the RAB20 gene; TdIF1 associates with the RAB20 promoter in cells and RAB20 transcription is reduced upon TdIF1 knockdown. SELEX, mutagenesis of DNA-binding residues, luciferase reporter assay, ChIP, siRNA knockdown with RT-qPCR PloS one Medium 23874396
2015 DNTTIP1 (TdIF1) genome-wide binding sites cluster in a 160-bp cassette containing 'AT-tract~palindrome~AT-tract'; TdIF1 upregulates transcription from promoters containing this motif primarily through the palindrome core. Target genes are enriched for roles in regulation of ossification. ChIP-seq, luciferase reporter assay, RT-qPCR Genes to cells : devoted to molecular & cellular mechanisms Medium 25619743
2015 DNTTIP1 serves as a dimeric chromatin-binding module within the MiDAC (HDAC1:MIDEAS:DNTTIP1) complex: its N-terminal domain forms a tight homodimerization domain with a novel fold that mediates assembly of the HDAC1:MIDEAS complex, while its C-terminal domain (SKI/SNO/DAC-related fold despite lacking sequence homology) mediates direct interaction with DNA and nucleosomes. Crystal structure determination, in vitro nucleosome binding assay, domain mapping by mutagenesis Nucleic acids research High 25653165
2020 Within the MiDAC complex, DNTTIP1 is essential for chromosome alignment during mitosis in cancer cell lines; mice lacking DNTTIP1 (or MIDEAS) die during late embryogenesis with identical phenotypes including heart malformation and haematopoietic failure. CryoEM structure of MiDAC reveals four copies of HDAC1 at the periphery with outward-facing active sites, consistent with a processive, multi-nucleosome deacetylase activity. CRISPR/siRNA loss-of-function in cancer cell lines, DNTTIP1 and MIDEAS knockout mice, cryoEM structure of intact MiDAC complex Nature communications High 32591534
2018 DNTTIP1 promotes tumoral growth in oral squamous cell carcinoma through its interaction with HDAC; DNTTIP1 knockdown causes G1 cell cycle arrest accompanied by increased p53 acetylation and upregulation of p21Cip1, indicating DNTTIP1-HDAC interaction suppresses p53 deacetylation to drive proliferation. siRNA knockdown, cell cycle analysis (flow cytometry), immunoblotting for acetylated p53 and p21, mouse xenograft model Laboratory investigation; a journal of technical methods and pathology Medium 29855544
2021 DNTTIP1 (TdIF1) interacts with LSD1 (lysine-specific demethylase 1) and recruits LSD1 to the E-cadherin promoter; TdIF1 knockdown reduces LSD1 enrichment at the E-cadherin promoter, leading to increased promoter histone methylation and elevated E-cadherin transcription, thereby suppressing EMT and metastasis in NSCLC cells. Co-immunoprecipitation, ChIP, siRNA knockdown, migration/invasion assays, mouse xenograft International journal of molecular sciences Medium 35008676
2022 DNTTIP1 promotes NPC metastasis by recruiting HDAC1 to the DUSP2 promoter, maintaining deacetylated histone H3K27 at that locus, suppressing DUSP2 expression, and thereby aberrantly activating ERK signaling and elevating MMP2 levels. ChIP assay, co-IP, luciferase reporter, RNA-seq, siRNA knockdown, in vivo xenograft, HDAC inhibitor treatment EBioMedicine Medium 35689852
2022 DNTTIP1 physically interacts with ZFP541, HDAC1/2, and is part of a complex required for pachytene progression in mouse spermatogenesis; ZFP541 depletion impairs this complex and disrupts meiotic gene activation. Co-immunoprecipitation, genetic KO in mice, spermatocyte phenotyping Journal of genetics and genomics = Yi chuan xue bao Medium 35341968
2025 DNTTIP1, together with MIDEAS, mediates assembly of the MiDAC complex; a cryoEM structure of MiDAC with a MIDEAS variant (p.Tyr654Ser) shows that the mutant displaces a conserved auto-inhibitory loop covering the HDAC active site, increasing deacetylase activity. Reciprocal gene expression changes in patient fibroblasts versus MiDAC-degraded cell lines confirm the hyperactive MiDAC drives a multisystem developmental disorder. CryoEM structure, patient-derived fibroblast transcriptomics, rapid degron-mediated MiDAC degradation cell line Nature communications High 41290615
2026 DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to the BMF promoter to silence BMF via H3K27 deacetylation; DNTTIP1 depletion causes H3K27 hyperacetylation at the BMF promoter, reactivates BMF expression, disrupts BCL2-mediated survival, and triggers coordinated autophagy and apoptosis in acute leukaemia cells. CUT&Tag, ATAC-seq, RNA-seq, ChIP-qPCR, siRNA/shRNA knockdown, 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 62 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 42 26156556
2022 DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway. EBioMedicine 33 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
2022 DNTTIP2 Expression is Associated with Macrophage Infiltration and Malignant Characteristics in Low-Grade Glioma. Pharmacogenomics and personalized medicine 13 35370417
2018 TdIF1: a putative oncogene in NSCLC tumor progression. Signal transduction and targeted therapy 13 30345081
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 12 32617195
2006 Direct binding of TReP-132 with TdT results in reduction of TdT activity. Genes to cells : devoted to molecular & cellular mechanisms 12 16371131
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
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 5 36417085
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
2021 A comprehensive analysis of different gene classes in pancreatic cancer: SIGLEC15 may be a promising immunotherapeutic target. Investigational new drugs 4 34515878
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
2026 DNTTIP1 drives leukaemogenesis through MiDAC-mediated epigenetic silencing of BMF. Clinical and translational medicine 0 41603084
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

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