{"gene":"DNTTIP1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"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.","method":"Yeast two-hybrid, co-elution by gel filtration, in vitro TdT activity assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus gel filtration co-elution plus in vitro activity assay in single study, but no mutagenesis or structural validation","pmids":["11473582"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Deletion mutagenesis, in vitro TdT activity assays, DNA binding assays","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis mapping functional domains, single lab but multiple orthogonal assays","pmids":["17663723"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Yeast two-hybrid, GST pull-down, immunoprecipitation, in vitro TdT activity assay, co-localization by fluorescence microscopy","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down and IP plus functional in vitro assay, single lab","pmids":["16371131"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, co-localization fluorescence microscopy, ubiquitylation assay in 293T cells","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down and IP plus functional ubiquitylation assay, single lab","pmids":["19930467"],"is_preprint":false},{"year":2013,"finding":"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.","method":"SELEX, mutagenesis of DNA-binding residues, luciferase reporter assay, ChIP, siRNA knockdown with RT-qPCR","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro SELEX plus mutagenesis plus ChIP plus functional reporter, single lab","pmids":["23874396"],"is_preprint":false},{"year":2015,"finding":"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.","method":"ChIP-seq, luciferase reporter assay, RT-qPCR","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq plus functional reporter assay, single lab","pmids":["25619743"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Crystal structure determination, in vitro nucleosome binding assay, domain mapping by mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of two DNTTIP1 domains with functional validation by nucleosome binding and complex assembly assays in single rigorous study","pmids":["25653165"],"is_preprint":false},{"year":2020,"finding":"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.","method":"CRISPR/siRNA loss-of-function in cancer cell lines, DNTTIP1 and MIDEAS knockout mice, cryoEM structure of intact MiDAC complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryoEM structure plus genetic KO in multiple organisms plus defined cellular phenotype, replicated across mouse and cell line models in single comprehensive study","pmids":["32591534"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown, cell cycle analysis (flow cytometry), immunoblotting for acetylated p53 and p21, mouse xenograft model","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cell cycle phenotype and molecular readout, single lab, multiple methods","pmids":["29855544"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, migration/invasion assays, mouse xenograft","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus ChIP plus functional rescue, single lab","pmids":["35008676"],"is_preprint":false},{"year":2022,"finding":"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.","method":"ChIP assay, co-IP, luciferase reporter, RNA-seq, siRNA knockdown, in vivo xenograft, HDAC inhibitor treatment","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus functional reporter plus in vivo validation, single lab","pmids":["35689852"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, genetic KO in mice, spermatocyte phenotyping","journal":"Journal of genetics and genomics = Yi chuan xue bao","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction evidence plus KO phenotype, single lab","pmids":["35341968"],"is_preprint":false},{"year":2025,"finding":"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.","method":"CryoEM structure, patient-derived fibroblast transcriptomics, rapid degron-mediated MiDAC degradation cell line","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryoEM structure of variant complex plus functional transcriptomic validation in patient cells plus degron control, multiple orthogonal methods","pmids":["41290615"],"is_preprint":false},{"year":2026,"finding":"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.","method":"CUT&Tag, ATAC-seq, RNA-seq, ChIP-qPCR, siRNA/shRNA knockdown, in vivo leukaemia mouse models, drug synergy assays","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multi-omics chromatin profiling plus ChIP-qPCR plus in vivo genetic validation, multiple orthogonal methods in single study","pmids":["41603084"],"is_preprint":false}],"current_model":"DNTTIP1 is the chromatin-targeting and dimerization subunit of the MiDAC histone deacetylase complex: its N-terminal domain forms a homodimer that scaffolds HDAC1/2 and MIDEAS assembly, while its C-terminal SKI/SNO/DAC-like domain binds DNA and nucleosomes; the intact complex positions four outward-facing HDAC1 active sites for processive deacetylation of multiple nucleosomes, silencing target genes (including DUSP2 and BMF) by maintaining deacetylated H3K27, and DNTTIP1 also binds and regulates TdT activity, recruits co-regulators such as LSD1 and BPOZ-2 to chromatin, and is essential for mitotic chromosome alignment, embryonic heart and haematopoietic development, and male meiotic progression."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2001,"claim":"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","pmids":["11473582"],"confidence":"Medium","gaps":["No mutagenesis defining the interaction interface","Identity of other ~232 kDa complex members not resolved"]},{"year":2006,"claim":"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","pmids":["16371131"],"confidence":"Medium","gaps":["Cellular consequences for V(D)J recombination not directly tested","Single-lab interaction data"]},{"year":2007,"claim":"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","pmids":["17663723"],"confidence":"High","gaps":["In vitro only; in vivo relevance to recombination not established","Structural basis of DNA selectivity not yet solved at this stage"]},{"year":2009,"claim":"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","pmids":["19930467"],"confidence":"Medium","gaps":["Endogenous TdT turnover via this axis not demonstrated","Overexpression-based ubiquitylation readout"]},{"year":2013,"claim":"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","pmids":["23874396"],"confidence":"Medium","gaps":["Mechanism of transcriptional activation not defined","Single target gene examined"]},{"year":2015,"claim":"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","pmids":["25619743"],"confidence":"Medium","gaps":["Co-factors mediating activation at these sites unresolved","Relationship to repressive MiDAC function not reconciled"]},{"year":2015,"claim":"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","pmids":["25653165"],"confidence":"High","gaps":["Structure of the intact assembled complex not yet determined","Genomic targets of the complex not mapped"]},{"year":2018,"claim":"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","pmids":["29855544"],"confidence":"Medium","gaps":["Whether p53 is a direct MiDAC substrate not shown","MiDAC complex context not directly tested here"]},{"year":2020,"claim":"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","pmids":["32591534"],"confidence":"High","gaps":["Direct substrate nucleosomes in cells not enumerated","How chromosome alignment is mechanistically controlled by deacetylation unresolved"]},{"year":2021,"claim":"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","pmids":["35008676"],"confidence":"Medium","gaps":["Whether LSD1 recruitment is MiDAC-dependent unclear","Single target locus"]},{"year":2022,"claim":"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","pmids":["35689852"],"confidence":"Medium","gaps":["Genome-wide scope of DNTTIP1-dependent H3K27 deacetylation not defined here","Single cancer context"]},{"year":2022,"claim":"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","pmids":["35341968"],"confidence":"Medium","gaps":["Direct DNTTIP1 contribution versus ZFP541 not dissected","Target genes governing meiotic arrest not fully defined"]},{"year":2025,"claim":"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","pmids":["41290615"],"confidence":"High","gaps":["DNTTIP1's specific contribution to the auto-inhibitory regulation not isolated","Causal DNTTIP1 variants in patients not reported here"]},{"year":2026,"claim":"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","pmids":["41603084"],"confidence":"High","gaps":["Whether BMF is a direct versus indirect target not fully separated","Generalization beyond leukaemia not tested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,4,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,7,10,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5,10,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,11]}],"complexes":["MiDAC (HDAC1:MIDEAS:DNTTIP1)"],"partners":["HDAC1","HDAC2","MIDEAS","TDT (DNTT)","LSD1","ZFP541","BPOZ-2","TREP-132"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H147","full_name":"Deoxynucleotidyltransferase terminal-interacting protein 1","aliases":["Terminal deoxynucleotidyltransferase-interacting factor 1","TdIF1","TdT-interacting factor 1"],"length_aa":329,"mass_kda":37.0,"function":"Increases DNTT terminal deoxynucleotidyltransferase activity (in vitro) (PubMed:11473582). Also acts as a transcriptional regulator, binding to the consensus sequence 5'-GNTGCATG-3' following an AT-tract. Associates with RAB20 promoter and positively regulates its transcription. Binds DNA and nucleosomes; may recruit HDAC1 complexes to nucleosomes or naked DNA","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H147/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNTTIP1","classification":"Not Classified","n_dependent_lines":29,"n_total_lines":1208,"dependency_fraction":0.024006622516556293},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101457","cell_line_id":"CID001022","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":1}],"interactors":[{"gene":"PPM1G","stoichiometry":0.2},{"gene":"ELMSAN1","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"LAS1L","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"BCAR2;TRERF1","stoichiometry":0.2},{"gene":"CDC16","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001022","total_profiled":1310},"omim":[{"mim_id":"621074","title":"MITOTIC DEACETYLASE-ASSOCIATED SANT DOMAIN PROTEIN; MIDEAS","url":"https://www.omim.org/entry/621074"},{"mim_id":"611388","title":"DEOXYNUCLEOTIDYLTRANSFERASE, TERMINAL, INTERACTING PROTEIN 1; DNTTIP1","url":"https://www.omim.org/entry/611388"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Supported"},{"location":"Mitotic chromosome","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNTTIP1"},"hgnc":{"alias_symbol":["dJ447F3.4","Tdif1"],"prev_symbol":["C20orf167"]},"alphafold":{"accession":"Q9H147","domains":[{"cath_id":"-","chopping":"62-126","consensus_level":"high","plddt":94.3594,"start":62,"end":126},{"cath_id":"-","chopping":"199-318","consensus_level":"high","plddt":82.3678,"start":199,"end":318}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H147","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H147-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H147-F1-predicted_aligned_error_v6.png","plddt_mean":68.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNTTIP1","jax_strain_url":"https://www.jax.org/strain/search?query=DNTTIP1"},"sequence":{"accession":"Q9H147","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H147.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H147/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H147"}},"corpus_meta":[{"pmid":"32591534","id":"PMC_32591534","title":"The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32591534","citation_count":62,"is_preprint":false},{"pmid":"25653165","id":"PMC_25653165","title":"Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25653165","citation_count":53,"is_preprint":false},{"pmid":"26156556","id":"PMC_26156556","title":"The extended AT-hook is a novel RNA binding motif.","date":"2015","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/26156556","citation_count":42,"is_preprint":false},{"pmid":"35689852","id":"PMC_35689852","title":"DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway.","date":"2022","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/35689852","citation_count":33,"is_preprint":false},{"pmid":"11473582","id":"PMC_11473582","title":"Terminal deoxynucleotidyltransferase directly interacts with a novel nuclear protein that is homologous to p65.","date":"2001","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/11473582","citation_count":28,"is_preprint":false},{"pmid":"29690867","id":"PMC_29690867","title":"Identification of genes directly responding to DLK1 signaling in Callipyge sheep.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29690867","citation_count":17,"is_preprint":false},{"pmid":"29855544","id":"PMC_29855544","title":"Critical role of deoxynucleotidyl transferase terminal interacting protein 1 in oral cancer.","date":"2018","source":"Laboratory investigation; 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TdIF1 contains AT-hook (HMG-I/Y) DNA binding domains and can bind single- and double-stranded DNA.\",\n      \"method\": \"Yeast two-hybrid, co-elution by gel filtration, in vitro TdT activity assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus gel filtration co-elution plus in vitro activity assay in single study, but no mutagenesis or structural validation\",\n      \"pmids\": [\"11473582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Deletion mutagenesis, in vitro TdT activity assays, DNA binding assays\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis mapping functional domains, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"17663723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, immunoprecipitation, in vitro TdT activity assay, co-localization by fluorescence microscopy\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down and IP plus functional in vitro assay, single lab\",\n      \"pmids\": [\"16371131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, co-localization fluorescence microscopy, ubiquitylation assay in 293T cells\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down and IP plus functional ubiquitylation assay, single lab\",\n      \"pmids\": [\"19930467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"SELEX, mutagenesis of DNA-binding residues, luciferase reporter assay, ChIP, siRNA knockdown with RT-qPCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro SELEX plus mutagenesis plus ChIP plus functional reporter, single lab\",\n      \"pmids\": [\"23874396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, luciferase reporter assay, RT-qPCR\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq plus functional reporter assay, single lab\",\n      \"pmids\": [\"25619743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, in vitro nucleosome binding assay, domain mapping by mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of two DNTTIP1 domains with functional validation by nucleosome binding and complex assembly assays in single rigorous study\",\n      \"pmids\": [\"25653165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/siRNA loss-of-function in cancer cell lines, DNTTIP1 and MIDEAS knockout mice, cryoEM structure of intact MiDAC complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryoEM structure plus genetic KO in multiple organisms plus defined cellular phenotype, replicated across mouse and cell line models in single comprehensive study\",\n      \"pmids\": [\"32591534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (flow cytometry), immunoblotting for acetylated p53 and p21, mouse xenograft model\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cell cycle phenotype and molecular readout, single lab, multiple methods\",\n      \"pmids\": [\"29855544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, migration/invasion assays, mouse xenograft\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus ChIP plus functional rescue, single lab\",\n      \"pmids\": [\"35008676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, co-IP, luciferase reporter, RNA-seq, siRNA knockdown, in vivo xenograft, HDAC inhibitor treatment\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus functional reporter plus in vivo validation, single lab\",\n      \"pmids\": [\"35689852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, genetic KO in mice, spermatocyte phenotyping\",\n      \"journal\": \"Journal of genetics and genomics = Yi chuan xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction evidence plus KO phenotype, single lab\",\n      \"pmids\": [\"35341968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"CryoEM structure, patient-derived fibroblast transcriptomics, rapid degron-mediated MiDAC degradation cell line\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryoEM structure of variant complex plus functional transcriptomic validation in patient cells plus degron control, multiple orthogonal methods\",\n      \"pmids\": [\"41290615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"CUT&Tag, ATAC-seq, RNA-seq, ChIP-qPCR, siRNA/shRNA knockdown, in vivo leukaemia mouse models, drug synergy assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multi-omics chromatin profiling plus ChIP-qPCR plus in vivo genetic validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41603084\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNTTIP1 is the chromatin-targeting and dimerization subunit of the MiDAC histone deacetylase complex: its N-terminal domain forms a homodimer that scaffolds HDAC1/2 and MIDEAS assembly, while its C-terminal SKI/SNO/DAC-like domain binds DNA and nucleosomes; the intact complex positions four outward-facing HDAC1 active sites for processive deacetylation of multiple nucleosomes, silencing target genes (including DUSP2 and BMF) by maintaining deacetylated H3K27, and DNTTIP1 also binds and regulates TdT activity, recruits co-regulators such as LSD1 and BPOZ-2 to chromatin, and is essential for mitotic chromosome alignment, embryonic heart and haematopoietic development, and male meiotic progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#6, #7]. 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 [#6]. Within the assembled MiDAC complex, four peripheral HDAC1 active sites face outward, consistent with processive, multi-nucleosome deacetylation [#7]. 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 [#10] and silencing BMF to sustain BCL2-mediated survival in acute leukaemia [#13]. 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 [#7]; the complex also requires DNTTIP1 for pachytene progression during male meiosis via a ZFP541-HDAC1/2 assembly [#11]. 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 [#12]. 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 [#0, #1], and it can recruit additional co-regulators including LSD1 and the CUL3 adaptor BPOZ-2 to chromatin [#9, #3].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, gel filtration co-elution, and in vitro TdT activity assay in thymocyte lysate\",\n      \"pmids\": [\"11473582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis defining the interaction interface\", \"Identity of other ~232 kDa complex members not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a regulatory triad showing DNTTIP1 and TReP-132 both bind TdT and co-localize, refining how TdT activity is negatively controlled during recombination.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, IP, in vitro TdT activity assay, and co-localization microscopy\",\n      \"pmids\": [\"16371131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequences for V(D)J recombination not directly tested\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped DNTTIP1's DNA-binding architecture and showed dsDNA competes TdT off the complex, mechanistically linking its DNA binding to TdT regulation.\",\n      \"evidence\": \"Deletion mutagenesis with in vitro TdT activity and DNA-binding assays\",\n      \"pmids\": [\"17663723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro only; in vivo relevance to recombination not established\", \"Structural basis of DNA selectivity not yet solved at this stage\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed DNTTIP1 couples TdT to the ubiquitin-proteasome system by recruiting the CUL3 adaptor BPOZ-2 into the nucleus.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, co-IP, co-localization, and ubiquitylation assay in 293T cells\",\n      \"pmids\": [\"19930467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous TdT turnover via this axis not demonstrated\", \"Overexpression-based ubiquitylation readout\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"SELEX, mutagenesis, luciferase reporter, ChIP, and siRNA knockdown with RT-qPCR\",\n      \"pmids\": [\"23874396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional activation not defined\", \"Single target gene examined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Generalized DNTTIP1's genomic targeting by defining a composite AT-tract/palindrome cassette driving its transcriptional upregulation of an ossification-related gene set.\",\n      \"evidence\": \"ChIP-seq, luciferase reporter, and RT-qPCR\",\n      \"pmids\": [\"25619743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-factors mediating activation at these sites unresolved\", \"Relationship to repressive MiDAC function not reconciled\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structures of two DNTTIP1 domains with nucleosome-binding and complex-assembly assays\",\n      \"pmids\": [\"25653165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the intact assembled complex not yet determined\", \"Genomic targets of the complex not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked DNTTIP1-HDAC activity to proliferation control, showing its loss arrests the cell cycle through p53 hyperacetylation and p21 induction.\",\n      \"evidence\": \"siRNA knockdown, flow cytometry, immunoblot for acetyl-p53/p21, and xenograft in oral squamous carcinoma\",\n      \"pmids\": [\"29855544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 is a direct MiDAC substrate not shown\", \"MiDAC complex context not directly tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"CryoEM of intact MiDAC, CRISPR/siRNA in cancer cells, and DNTTIP1/MIDEAS knockout mice\",\n      \"pmids\": [\"32591534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate nucleosomes in cells not enumerated\", \"How chromosome alignment is mechanistically controlled by deacetylation unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed DNTTIP1 recruits the demethylase LSD1 to a target promoter, expanding its co-regulator repertoire beyond HDACs and linking it to EMT suppression.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, migration/invasion assays, and xenograft in NSCLC\",\n      \"pmids\": [\"35008676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LSD1 recruitment is MiDAC-dependent unclear\", \"Single target locus\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated locus-specific gene silencing by DNTTIP1, recruiting HDAC1 to the DUSP2 promoter to maintain H3K27 deacetylation and aberrantly activate ERK signaling in metastasis.\",\n      \"evidence\": \"ChIP, co-IP, luciferase reporter, RNA-seq, siRNA, xenograft, and HDAC inhibitor treatment\",\n      \"pmids\": [\"35689852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide scope of DNTTIP1-dependent H3K27 deacetylation not defined here\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended DNTTIP1's complex membership to a ZFP541-HDAC1/2 assembly required for meiotic pachytene progression in spermatogenesis.\",\n      \"evidence\": \"Co-IP and genetic knockout with spermatocyte phenotyping in mice\",\n      \"pmids\": [\"35341968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNTTIP1 contribution versus ZFP541 not dissected\", \"Target genes governing meiotic arrest not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"CryoEM of variant complex, patient fibroblast transcriptomics, and degron-mediated MiDAC degradation\",\n      \"pmids\": [\"41290615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNTTIP1's specific contribution to the auto-inhibitory regulation not isolated\", \"Causal DNTTIP1 variants in patients not reported here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed DNTTIP1 acts as a MiDAC scaffold that silences BMF via H3K27 deacetylation, defining a therapeutically actionable apoptosis/autophagy axis in leukaemia.\",\n      \"evidence\": \"CUT&Tag, ATAC-seq, RNA-seq, ChIP-qPCR, knockdown, in vivo leukaemia models, and drug synergy assays\",\n      \"pmids\": [\"41603084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BMF is a direct versus indirect target not fully separated\", \"Generalization beyond leukaemia not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 7, 10, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5, 10, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [\"MiDAC (HDAC1:MIDEAS:DNTTIP1)\"],\n    \"partners\": [\"HDAC1\", \"HDAC2\", \"MIDEAS\", \"TdT (DNTT)\", \"LSD1\", \"ZFP541\", \"BPOZ-2\", \"TReP-132\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}