{"gene":"TASP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"Taspase1-dependent proteolytic cleavage of MLL1 destabilizes MLL1; loss of taspase1 increases uncleaved MLL1 stability and its association with chromatin, displacing MLL chimeras in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating cleavage; pharmacological CKII inhibition blocks MLL1 processing and increases MLL1 stability.","method":"Genetic loss-of-function (taspase1 KO), chromatin fractionation/ChIP, pharmacological inhibition (CKII inhibitor), in vivo MLL-AF9 mouse leukemia model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, genetic KO, pharmacological inhibition, in vivo mouse model) in a single rigorous study establishing mechanism","pmids":["30573454"],"is_preprint":false},{"year":2014,"finding":"Taspase1 cleaves MLL1 in vivo; this cleavage is required for MMTV-neu-driven breast tumorigenesis by enabling expression of cyclins E and A. Mice with homozygous noncleavable MLL alleles (MLL-nc/nc) are protected from HER2/neu-driven mammary tumor formation, establishing MLL as the primary Taspase1 substrate in this oncogenic axis.","method":"Conditional knockout mice (MMTV-neu;MMTV-cre;Tasp1(F/-)), transgenic knockin of noncleavable MLL (MLL-nc/nc), knockdown-rescue experiments in HER2+ cell lines","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models (cKO and knockin) with orthogonal cell-line validation, replicated across breast cancer contexts","pmids":["25267403"],"is_preprint":false},{"year":2015,"finding":"Taspase1-mediated cleavage of TFIIA is the principal substrate event orchestrating craniofacial morphogenesis. Loss of TASP1 causes catastrophic craniofacial malformations; uncleaved TFIIA accumulates at p16Ink4a and p19Arf promoters and drives their transcription, limiting cell proliferation. Genetic reduction of Cdkn2a (especially p16Ink4a) markedly rescues craniofacial anomalies in TASP1-deficient mice.","method":"Genetic epistasis (Tasp1 KO × Cdkn2a KO compound mutants), knockin of noncleavable TASP1 substrates (TFIIA vs. MLL), ChIP analysis of p16/p19 promoters","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic epistasis with compound mutants, substrate-specific knockin alleles, and ChIP, all in vivo, multiple orthogonal approaches","pmids":["25664857"],"is_preprint":false},{"year":2021,"finding":"Taspase1-mediated cleavage of TFIIAα-β (rather than MLL1 or MLL2) is required for proper fetal liver hematopoietic stem cell self-renewal/quiescence and correct segmental identities of the axial skeleton in mouse embryos. Noncleavable TFIIAα-β knockin mice displayed more pronounced fetal liver and axial skeleton defects than noncleavable MLL1 or MLL2 knockins.","method":"Genetic deletion (Tasp1 KO), substrate-specific noncleavable knockin mice (TFIIAα-β, MLL1, MLL2), phenotypic comparison of embryonic hematopoiesis and skeletal segmentation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple substrate-specific knockin alleles in vivo with orthogonal phenotypic readouts, direct comparison of substrates","pmids":["34156981"],"is_preprint":false},{"year":2020,"finding":"TASP1 (Taspase1) cleaves REV3L, the catalytic subunit of DNA polymerase ζ, generating an N-terminal 70-kDa fragment and a C-terminal polymerase catalytic domain fragment. This proteolytic cleavage prevents ubiquitination and proteasome-mediated degradation of REV3L, thereby stabilizing it. Endogenous REV3L point mutations that compromise TASP1 cleavage markedly impair cellular responses to UV and cisplatin-induced DNA lesions.","method":"In vitro cleavage assay, endogenous knockin point mutations (HCT116), ubiquitination assay, DNA damage response assays (UV, cisplatin)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of cleavage, endogenous knockin mutations with functional phenotypic readout, multiple orthogonal methods in one study","pmids":["32064513"],"is_preprint":false},{"year":2022,"finding":"Taspase1 (TASP1) cleaves the unconventional myosin Myo1f. Myo1f is a nucleo-cytoplasmic shuttle protein processed by nuclear Taspase1, and Myo1f promotes filopodia formation, cellular adhesion, and migration. Taspase1-mediated proteolysis of Myo1f antagonizes filopodia formation; inverse correlation between Myo1f concentration and TASP1 expression was observed in macrophages versus monocytes.","method":"Co-IP/pulldown to identify Myo1f as substrate, cleavage assays, live-cell imaging of filopodia, knockdown/overexpression experiments, nuclear fractionation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — substrate identification with cleavage assay and functional filopodia readout, single lab with multiple approaches but abstract-level description","pmids":["35601920"],"is_preprint":false},{"year":2019,"finding":"Homozygous loss-of-function variants in TASP1 (including active-site missense p.Thr234Met, deletion of exons 5-11, and nonsense p.Arg67*) cause a recognizable developmental syndrome. TASP1 encodes taspase1, which activates KMT2A and KMT2D (histone methyltransferases) by proteolytic cleavage. Loss of TASP1 function phenocopies aspects of Wiedemann-Steiner (KMT2A) and Kabuki (KMT2D) syndromes, consistent with TASP1 acting upstream of these methyltransferases.","method":"Whole-exome sequencing, active-site missense variant in patients (p.Thr234Met affects catalytic residue), clinical phenotype comparison with KMT2A/KMT2D syndrome patients","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — active-site variant functionally implicates catalytic mechanism, epistatic inference from syndrome overlap, but no direct biochemical reconstitution in this paper","pmids":["31209944"],"is_preprint":false},{"year":2022,"finding":"TASP1 deficiency leads to HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA in patient fibroblasts (by western blot, RNA-seq, and proteomics). TASP1 loss produces a distinct DNA methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles. Zebrafish tasp1 knockout caused smaller head size and abnormal cranial cartilage formation.","method":"Western blot (absence of TASP1 protein), RNA-seq, proteomics from patient fibroblasts, methylome analysis, zebrafish CRISPR knockout","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics in patient-derived cells plus zebrafish KO, but each arm is a single experiment in one study","pmids":["35512351"],"is_preprint":false},{"year":2018,"finding":"The C. elegans tasp-1 gene (ortholog of TASP1) modulates levels of ELT-2 protein in the early endoderm; loss of tasp-1 leads to modest increases in ELT-2 levels, consistent with a role in regulating transcription factor abundance. tasp-1 was identified as a suppressor of a lethal end-1 end-3 mutation, verified by RNAi and CRISPR/Cas9.","method":"Genetic suppressor screen, RNAi, CRISPR/Cas9 loss-of-function in C. elegans","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (suppressor screen) verified by two independent methods (RNAi + CRISPR), but functional mechanism is inferred rather than biochemically characterized","pmids":["29593072"],"is_preprint":false},{"year":2008,"finding":"HNF4alpha splice variants transcriptionally regulate TASP1 expression; TASP1 is a downstream target of HNF4alpha in hepatocellular carcinoma, with induced expression in mouse and human HCCs, identified by chromatin immunoprecipitation followed by cloning/sequencing, EMSA, and qRT-PCR.","method":"Chromatin immunoprecipitation (ChIP), EMSA, qRT-PCR, Western blotting, immunohistochemistry","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA demonstrate direct HNF4alpha binding to TASP1 locus, multiple orthogonal methods, single lab","pmids":["18395097"],"is_preprint":false}],"current_model":"TASP1 encodes Taspase1, a highly conserved nuclear threonine endopeptidase that site-specifically cleaves multiple nuclear substrates—including MLL1/KMT2A, MLL2/KMT2D, TFIIA, and REV3L—to regulate their stability, chromatin association, and transcriptional activity, thereby orchestrating cell proliferation, hematopoiesis, craniofacial morphogenesis, axial skeletal patterning, DNA damage tolerance, and filopodia dynamics; its cleavage of MLL1 is facilitated by prior CKII phosphorylation, and loss of TASP1 function in humans causes Suleiman-El-Hattab syndrome through failure to activate KMT2A and KMT2D histone methyltransferases."},"narrative":{"mechanistic_narrative":"TASP1 (Taspase1) is a nuclear endopeptidase that site-specifically cleaves multiple nuclear substrates to control their stability and activity, thereby coordinating cell proliferation, hematopoiesis, craniofacial and axial skeletal patterning, and DNA damage tolerance [PMID:30573454, PMID:25664857, PMID:34156981]. Its substrate repertoire spans the histone methyltransferase MLL1/KMT2A, whose cleavage destabilizes MLL1 and limits its chromatin association and is required for HER2/neu-driven mammary tumorigenesis via cyclin E/A expression; this MLL1 processing is facilitated by prior CKII phosphorylation near the cleavage site [PMID:30573454, PMID:25267403]. Through cleavage of the general transcription factor TFIIA, Taspase1 governs craniofacial morphogenesis—uncleaved TFIIA accumulates at the Cdkn2a (p16Ink4a/p19Arf) promoters to repress proliferation—and is the principal substrate event for fetal liver hematopoietic stem cell self-renewal and correct axial skeletal segmental identity [PMID:25664857, PMID:34156981]. Beyond gene regulation, Taspase1 cleaves the DNA polymerase ζ catalytic subunit REV3L to protect it from ubiquitin-proteasome degradation, supporting cellular responses to UV and cisplatin lesions, and processes the unconventional myosin Myo1f to antagonize filopodia formation [PMID:32064513, PMID:35601920]. In humans, homozygous loss-of-function and active-site missense (p.Thr234Met) variants in TASP1 cause a developmental syndrome with failure to activate KMT2A and KMT2D, downregulation of HOX genes, and a DNA methylation signature intermediate between control and Kabuki syndrome [PMID:31209944, PMID:35512351].","teleology":[{"year":2008,"claim":"Established an upstream transcriptional input to TASP1, showing it is a HNF4alpha target gene induced in hepatocellular carcinoma, linking its expression to a liver oncogenic program.","evidence":"ChIP, EMSA, qRT-PCR and IHC in mouse and human HCC","pmids":["18395097"],"confidence":"Medium","gaps":["Does not address Taspase1 enzymatic function","No demonstration that TASP1 induction is required for HCC phenotypes"]},{"year":2014,"claim":"Identified MLL1 as the functionally decisive Taspase1 substrate in an oncogenic context, showing that MLL cleavage enables cyclin E/A expression required for HER2/neu mammary tumorigenesis.","evidence":"Conditional Tasp1 knockout and noncleavable MLL knockin mice with cell-line rescue","pmids":["25267403"],"confidence":"High","gaps":["Does not resolve which substrates dominate in non-tumor tissues","Mechanism of how uncleaved MLL alters cyclin promoters not fully detailed"]},{"year":2015,"claim":"Resolved substrate specificity in development by showing TFIIA, not MLL, is the principal Taspase1 substrate driving craniofacial morphogenesis through Cdkn2a-dependent control of proliferation.","evidence":"Genetic epistasis with Cdkn2a compound mutants, substrate-specific noncleavable knockins, and promoter ChIP in mice","pmids":["25664857"],"confidence":"High","gaps":["Does not establish how uncleaved TFIIA selectively activates p16/p19 promoters","Tissue-specific substrate hierarchy outside craniofacial structures unaddressed"]},{"year":2018,"claim":"Defined the regulatory mechanism of MLL1 cleavage, showing CKII phosphorylation primes MLL1 and that Taspase1 cleavage destabilizes MLL1 and restricts its chromatin binding, with consequences for leukemic MLL chimeras.","evidence":"Taspase1 KO, chromatin fractionation/ChIP, CKII pharmacological inhibition, MLL-AF9 mouse leukemia model","pmids":["30573454"],"confidence":"High","gaps":["Whether CKII priming applies to other substrates not tested","Quantitative contribution of MLL1 displacement to leukemia outcome unresolved"]},{"year":2018,"claim":"Provided cross-species evidence that the Taspase1 ortholog regulates transcription factor abundance, with C. elegans tasp-1 loss modestly increasing the endoderm GATA factor ELT-2.","evidence":"Genetic suppressor screen with RNAi and CRISPR/Cas9 validation in C. elegans","pmids":["29593072"],"confidence":"Medium","gaps":["Whether ELT-2 is a direct cleavage substrate not determined","Effect size is modest and mechanism inferred rather than biochemical"]},{"year":2019,"claim":"Connected TASP1 loss to a human Mendelian disease, identifying active-site and loss-of-function variants and placing Taspase1 upstream of KMT2A/KMT2D activation, phenocopying Wiedemann-Steiner and Kabuki syndromes.","evidence":"Whole-exome sequencing with active-site missense (p.Thr234Met) and clinical phenotype comparison","pmids":["31209944"],"confidence":"Medium","gaps":["No biochemical reconstitution of variant catalytic defects in this study","Relative contribution of KMT2A vs KMT2D to the human phenotype not separated"]},{"year":2020,"claim":"Expanded the substrate repertoire beyond transcription to DNA damage tolerance, showing Taspase1 cleaves REV3L (Pol ζ catalytic subunit) to shield it from proteasomal degradation and sustain UV/cisplatin lesion responses.","evidence":"In vitro cleavage assay, endogenous knockin point mutations in HCT116, ubiquitination and DNA damage response assays","pmids":["32064513"],"confidence":"High","gaps":["How cleavage protects against ubiquitination mechanistically unclear","In vivo relevance of REV3L cleavage not established"]},{"year":2022,"claim":"Characterized the human disease at molecular resolution, showing TASP1 loss downregulates HOX genes, dysregulates TFIIA, and produces a distinct DNA methylation signature, with zebrafish KO reproducing cranial cartilage defects.","evidence":"Western blot, RNA-seq, proteomics and methylome of patient fibroblasts plus zebrafish CRISPR knockout","pmids":["35512351"],"confidence":"Medium","gaps":["Causal chain from TFIIA dysregulation to HOX downregulation not dissected","Each omics arm is a single experiment"]},{"year":2022,"claim":"Added a cytoskeletal dimension by identifying the nucleo-cytoplasmic shuttle myosin Myo1f as a Taspase1 substrate whose cleavage antagonizes filopodia formation and migration.","evidence":"Co-IP/pulldown substrate identification, cleavage assays, live-cell filopodia imaging, and nuclear fractionation","pmids":["35601920"],"confidence":"Medium","gaps":["Reciprocal validation and structural cleavage site mapping limited","Physiological significance of the macrophage/monocyte correlation untested"]},{"year":null,"claim":"How Taspase1 selects among its substrates in a given tissue, and what governs its substrate hierarchy beyond CKII priming of MLL1, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule for substrate prioritization across tissues","Structural basis of cleavage-site recognition not described in the corpus","Regulation of Taspase1 activity beyond HNF4alpha transcriptional control and CKII priming unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]}],"complexes":[],"partners":["KMT2A","KMT2D","TFIIA","REV3L","MYO1F"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6P5","full_name":"Threonine aspartase 1","aliases":[],"length_aa":420,"mass_kda":44.5,"function":"Protease responsible for KMT2A/MLL1 processing and activation (PubMed:14636557). It also activates KMT2D/MLL2 (By similarity). Through substrate activation, it controls the expression of HOXA genes, and the expression of key cell cycle regulators including CCNA1, CCNB1, CCNE1 and CDKN2A (By similarity) (PubMed:14636557)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H6P5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TASP1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TASP1","total_profiled":1310},"omim":[{"mim_id":"618950","title":"SULEIMAN-EL-HATTAB SYNDROME; SULEHS","url":"https://www.omim.org/entry/618950"},{"mim_id":"608270","title":"THREONINE ASPARTASE 1; TASP1","url":"https://www.omim.org/entry/608270"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":27.3}],"url":"https://www.proteinatlas.org/search/TASP1"},"hgnc":{"alias_symbol":["FLJ20212","dJ585I14.2"],"prev_symbol":["C20orf13"]},"alphafold":{"accession":"Q9H6P5","domains":[{"cath_id":"3.60.20.30","chopping":"44-129_232-353_361-417","consensus_level":"high","plddt":95.7066,"start":44,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6P5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6P5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6P5-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TASP1","jax_strain_url":"https://www.jax.org/strain/search?query=TASP1"},"sequence":{"accession":"Q9H6P5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6P5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6P5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6P5"}},"corpus_meta":[{"pmid":"32071545","id":"PMC_32071545","title":"TASP1 Promotes Gallbladder Cancer Cell Proliferation and Metastasis by Up-regulating FAM49B via PI3K/AKT Pathway.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32071545","citation_count":31,"is_preprint":false},{"pmid":"30573454","id":"PMC_30573454","title":"Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/30573454","citation_count":29,"is_preprint":false},{"pmid":"18395097","id":"PMC_18395097","title":"EPS15R, TASP1, and PRPF3 are novel disease candidate genes targeted by HNF4alpha splice variants in hepatocellular carcinomas.","date":"2008","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18395097","citation_count":28,"is_preprint":false},{"pmid":"25267403","id":"PMC_25267403","title":"Taspase1 cleaves MLL1 to activate cyclin E for HER2/neu breast tumorigenesis.","date":"2014","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25267403","citation_count":28,"is_preprint":false},{"pmid":"33689574","id":"PMC_33689574","title":"Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer.","date":"2021","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33689574","citation_count":27,"is_preprint":false},{"pmid":"35713103","id":"PMC_35713103","title":"Disorders of histone methylation: Molecular basis and clinical syndromes.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35713103","citation_count":23,"is_preprint":false},{"pmid":"25664857","id":"PMC_25664857","title":"Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25664857","citation_count":22,"is_preprint":false},{"pmid":"27308523","id":"PMC_27308523","title":"Taspase 1: A protease with many biological surprises.","date":"2015","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27308523","citation_count":21,"is_preprint":false},{"pmid":"34068162","id":"PMC_34068162","title":"Genome-Wide Association Study Provides Insights into Important Genes for Reproductive Traits in Nelore Cattle.","date":"2021","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/34068162","citation_count":17,"is_preprint":false},{"pmid":"26200114","id":"PMC_26200114","title":"Integrative Analysis of the Developing Postnatal Mouse Heart Transcriptome.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26200114","citation_count":15,"is_preprint":false},{"pmid":"33767369","id":"PMC_33767369","title":"Genome-wide association studies demonstrate that TASP1 contributes to increased muscle fiber diameter.","date":"2021","source":"Heredity","url":"https://pubmed.ncbi.nlm.nih.gov/33767369","citation_count":14,"is_preprint":false},{"pmid":"31209944","id":"PMC_31209944","title":"Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31209944","citation_count":11,"is_preprint":false},{"pmid":"29633245","id":"PMC_29633245","title":"TASP1 is deleted in an infant with developmental delay, microcephaly, distinctive facial features, and multiple congenital anomalies.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29633245","citation_count":11,"is_preprint":false},{"pmid":"37650943","id":"PMC_37650943","title":"Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37650943","citation_count":9,"is_preprint":false},{"pmid":"34012990","id":"PMC_34012990","title":"TASP1 Promotes Proliferation and Migration in Gastric Cancer via EMT and AKT/P-AKT Pathway.","date":"2021","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/34012990","citation_count":7,"is_preprint":false},{"pmid":"35512351","id":"PMC_35512351","title":"Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35512351","citation_count":7,"is_preprint":false},{"pmid":"32064513","id":"PMC_32064513","title":"Site-specific proteolytic cleavage prevents ubiquitination and degradation of human REV3L, the catalytic subunit of DNA polymerase 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Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/38709271","citation_count":5,"is_preprint":false},{"pmid":"35601920","id":"PMC_35601920","title":"The Taspase1/Myosin1f-axis regulates filopodia dynamics.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35601920","citation_count":5,"is_preprint":false},{"pmid":"34156981","id":"PMC_34156981","title":"Taspase1 orchestrates fetal liver hematopoietic stem cell and vertebrae fates by cleaving TFIIA.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34156981","citation_count":5,"is_preprint":false},{"pmid":"37284894","id":"PMC_37284894","title":"Circ_0059457 Promotes Proliferation, Metastasis, Sphere Formation and Glycolysis in Breast Cancer Cells by Sponging miR-140-3p to Regulate UBE2C.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37284894","citation_count":4,"is_preprint":false},{"pmid":"29593072","id":"PMC_29593072","title":"A Strategy To Isolate Modifiers of Caenorhabditis elegans Lethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2.","date":"2018","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29593072","citation_count":3,"is_preprint":false},{"pmid":"37474017","id":"PMC_37474017","title":"Long-term follow-up and novel variant in Suleiman-El-Hattab syndrome: Expanding the genotypic and clinical spectrum of a rare neurodevelopmental disorder.","date":"2023","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37474017","citation_count":1,"is_preprint":false},{"pmid":"41870130","id":"PMC_41870130","title":"Enhancing cancer classification accuracy with a self-attention network using panel capture sequencing data.","date":"2026","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/41870130","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14568,"output_tokens":3049,"usd":0.04472,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10389,"output_tokens":3348,"usd":0.067822,"stage2_stop_reason":"end_turn"},"total_usd":0.112542,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Taspase1-dependent proteolytic cleavage of MLL1 destabilizes MLL1; loss of taspase1 increases uncleaved MLL1 stability and its association with chromatin, displacing MLL chimeras in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating cleavage; pharmacological CKII inhibition blocks MLL1 processing and increases MLL1 stability.\",\n      \"method\": \"Genetic loss-of-function (taspase1 KO), chromatin fractionation/ChIP, pharmacological inhibition (CKII inhibitor), in vivo MLL-AF9 mouse leukemia model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, genetic KO, pharmacological inhibition, in vivo mouse model) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"30573454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Taspase1 cleaves MLL1 in vivo; this cleavage is required for MMTV-neu-driven breast tumorigenesis by enabling expression of cyclins E and A. Mice with homozygous noncleavable MLL alleles (MLL-nc/nc) are protected from HER2/neu-driven mammary tumor formation, establishing MLL as the primary Taspase1 substrate in this oncogenic axis.\",\n      \"method\": \"Conditional knockout mice (MMTV-neu;MMTV-cre;Tasp1(F/-)), transgenic knockin of noncleavable MLL (MLL-nc/nc), knockdown-rescue experiments in HER2+ cell lines\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models (cKO and knockin) with orthogonal cell-line validation, replicated across breast cancer contexts\",\n      \"pmids\": [\"25267403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Taspase1-mediated cleavage of TFIIA is the principal substrate event orchestrating craniofacial morphogenesis. Loss of TASP1 causes catastrophic craniofacial malformations; uncleaved TFIIA accumulates at p16Ink4a and p19Arf promoters and drives their transcription, limiting cell proliferation. Genetic reduction of Cdkn2a (especially p16Ink4a) markedly rescues craniofacial anomalies in TASP1-deficient mice.\",\n      \"method\": \"Genetic epistasis (Tasp1 KO × Cdkn2a KO compound mutants), knockin of noncleavable TASP1 substrates (TFIIA vs. MLL), ChIP analysis of p16/p19 promoters\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic epistasis with compound mutants, substrate-specific knockin alleles, and ChIP, all in vivo, multiple orthogonal approaches\",\n      \"pmids\": [\"25664857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Taspase1-mediated cleavage of TFIIAα-β (rather than MLL1 or MLL2) is required for proper fetal liver hematopoietic stem cell self-renewal/quiescence and correct segmental identities of the axial skeleton in mouse embryos. Noncleavable TFIIAα-β knockin mice displayed more pronounced fetal liver and axial skeleton defects than noncleavable MLL1 or MLL2 knockins.\",\n      \"method\": \"Genetic deletion (Tasp1 KO), substrate-specific noncleavable knockin mice (TFIIAα-β, MLL1, MLL2), phenotypic comparison of embryonic hematopoiesis and skeletal segmentation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple substrate-specific knockin alleles in vivo with orthogonal phenotypic readouts, direct comparison of substrates\",\n      \"pmids\": [\"34156981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TASP1 (Taspase1) cleaves REV3L, the catalytic subunit of DNA polymerase ζ, generating an N-terminal 70-kDa fragment and a C-terminal polymerase catalytic domain fragment. This proteolytic cleavage prevents ubiquitination and proteasome-mediated degradation of REV3L, thereby stabilizing it. Endogenous REV3L point mutations that compromise TASP1 cleavage markedly impair cellular responses to UV and cisplatin-induced DNA lesions.\",\n      \"method\": \"In vitro cleavage assay, endogenous knockin point mutations (HCT116), ubiquitination assay, DNA damage response assays (UV, cisplatin)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of cleavage, endogenous knockin mutations with functional phenotypic readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32064513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Taspase1 (TASP1) cleaves the unconventional myosin Myo1f. Myo1f is a nucleo-cytoplasmic shuttle protein processed by nuclear Taspase1, and Myo1f promotes filopodia formation, cellular adhesion, and migration. Taspase1-mediated proteolysis of Myo1f antagonizes filopodia formation; inverse correlation between Myo1f concentration and TASP1 expression was observed in macrophages versus monocytes.\",\n      \"method\": \"Co-IP/pulldown to identify Myo1f as substrate, cleavage assays, live-cell imaging of filopodia, knockdown/overexpression experiments, nuclear fractionation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — substrate identification with cleavage assay and functional filopodia readout, single lab with multiple approaches but abstract-level description\",\n      \"pmids\": [\"35601920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Homozygous loss-of-function variants in TASP1 (including active-site missense p.Thr234Met, deletion of exons 5-11, and nonsense p.Arg67*) cause a recognizable developmental syndrome. TASP1 encodes taspase1, which activates KMT2A and KMT2D (histone methyltransferases) by proteolytic cleavage. Loss of TASP1 function phenocopies aspects of Wiedemann-Steiner (KMT2A) and Kabuki (KMT2D) syndromes, consistent with TASP1 acting upstream of these methyltransferases.\",\n      \"method\": \"Whole-exome sequencing, active-site missense variant in patients (p.Thr234Met affects catalytic residue), clinical phenotype comparison with KMT2A/KMT2D syndrome patients\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — active-site variant functionally implicates catalytic mechanism, epistatic inference from syndrome overlap, but no direct biochemical reconstitution in this paper\",\n      \"pmids\": [\"31209944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TASP1 deficiency leads to HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA in patient fibroblasts (by western blot, RNA-seq, and proteomics). TASP1 loss produces a distinct DNA methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles. Zebrafish tasp1 knockout caused smaller head size and abnormal cranial cartilage formation.\",\n      \"method\": \"Western blot (absence of TASP1 protein), RNA-seq, proteomics from patient fibroblasts, methylome analysis, zebrafish CRISPR knockout\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics in patient-derived cells plus zebrafish KO, but each arm is a single experiment in one study\",\n      \"pmids\": [\"35512351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C. elegans tasp-1 gene (ortholog of TASP1) modulates levels of ELT-2 protein in the early endoderm; loss of tasp-1 leads to modest increases in ELT-2 levels, consistent with a role in regulating transcription factor abundance. tasp-1 was identified as a suppressor of a lethal end-1 end-3 mutation, verified by RNAi and CRISPR/Cas9.\",\n      \"method\": \"Genetic suppressor screen, RNAi, CRISPR/Cas9 loss-of-function in C. elegans\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (suppressor screen) verified by two independent methods (RNAi + CRISPR), but functional mechanism is inferred rather than biochemically characterized\",\n      \"pmids\": [\"29593072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HNF4alpha splice variants transcriptionally regulate TASP1 expression; TASP1 is a downstream target of HNF4alpha in hepatocellular carcinoma, with induced expression in mouse and human HCCs, identified by chromatin immunoprecipitation followed by cloning/sequencing, EMSA, and qRT-PCR.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), EMSA, qRT-PCR, Western blotting, immunohistochemistry\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA demonstrate direct HNF4alpha binding to TASP1 locus, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18395097\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TASP1 encodes Taspase1, a highly conserved nuclear threonine endopeptidase that site-specifically cleaves multiple nuclear substrates—including MLL1/KMT2A, MLL2/KMT2D, TFIIA, and REV3L—to regulate their stability, chromatin association, and transcriptional activity, thereby orchestrating cell proliferation, hematopoiesis, craniofacial morphogenesis, axial skeletal patterning, DNA damage tolerance, and filopodia dynamics; its cleavage of MLL1 is facilitated by prior CKII phosphorylation, and loss of TASP1 function in humans causes Suleiman-El-Hattab syndrome through failure to activate KMT2A and KMT2D histone methyltransferases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TASP1 (Taspase1) is a nuclear endopeptidase that site-specifically cleaves multiple nuclear substrates to control their stability and activity, thereby coordinating cell proliferation, hematopoiesis, craniofacial and axial skeletal patterning, and DNA damage tolerance [#0, #2, #3]. Its substrate repertoire spans the histone methyltransferase MLL1/KMT2A, whose cleavage destabilizes MLL1 and limits its chromatin association and is required for HER2/neu-driven mammary tumorigenesis via cyclin E/A expression; this MLL1 processing is facilitated by prior CKII phosphorylation near the cleavage site [#0, #1]. Through cleavage of the general transcription factor TFIIA, Taspase1 governs craniofacial morphogenesis—uncleaved TFIIA accumulates at the Cdkn2a (p16Ink4a/p19Arf) promoters to repress proliferation—and is the principal substrate event for fetal liver hematopoietic stem cell self-renewal and correct axial skeletal segmental identity [#2, #3]. Beyond gene regulation, Taspase1 cleaves the DNA polymerase ζ catalytic subunit REV3L to protect it from ubiquitin-proteasome degradation, supporting cellular responses to UV and cisplatin lesions, and processes the unconventional myosin Myo1f to antagonize filopodia formation [#4, #5]. In humans, homozygous loss-of-function and active-site missense (p.Thr234Met) variants in TASP1 cause a developmental syndrome with failure to activate KMT2A and KMT2D, downregulation of HOX genes, and a DNA methylation signature intermediate between control and Kabuki syndrome [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established an upstream transcriptional input to TASP1, showing it is a HNF4alpha target gene induced in hepatocellular carcinoma, linking its expression to a liver oncogenic program.\",\n      \"evidence\": \"ChIP, EMSA, qRT-PCR and IHC in mouse and human HCC\",\n      \"pmids\": [\"18395097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address Taspase1 enzymatic function\", \"No demonstration that TASP1 induction is required for HCC phenotypes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified MLL1 as the functionally decisive Taspase1 substrate in an oncogenic context, showing that MLL cleavage enables cyclin E/A expression required for HER2/neu mammary tumorigenesis.\",\n      \"evidence\": \"Conditional Tasp1 knockout and noncleavable MLL knockin mice with cell-line rescue\",\n      \"pmids\": [\"25267403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which substrates dominate in non-tumor tissues\", \"Mechanism of how uncleaved MLL alters cyclin promoters not fully detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved substrate specificity in development by showing TFIIA, not MLL, is the principal Taspase1 substrate driving craniofacial morphogenesis through Cdkn2a-dependent control of proliferation.\",\n      \"evidence\": \"Genetic epistasis with Cdkn2a compound mutants, substrate-specific noncleavable knockins, and promoter ChIP in mice\",\n      \"pmids\": [\"25664857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish how uncleaved TFIIA selectively activates p16/p19 promoters\", \"Tissue-specific substrate hierarchy outside craniofacial structures unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the regulatory mechanism of MLL1 cleavage, showing CKII phosphorylation primes MLL1 and that Taspase1 cleavage destabilizes MLL1 and restricts its chromatin binding, with consequences for leukemic MLL chimeras.\",\n      \"evidence\": \"Taspase1 KO, chromatin fractionation/ChIP, CKII pharmacological inhibition, MLL-AF9 mouse leukemia model\",\n      \"pmids\": [\"30573454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CKII priming applies to other substrates not tested\", \"Quantitative contribution of MLL1 displacement to leukemia outcome unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided cross-species evidence that the Taspase1 ortholog regulates transcription factor abundance, with C. elegans tasp-1 loss modestly increasing the endoderm GATA factor ELT-2.\",\n      \"evidence\": \"Genetic suppressor screen with RNAi and CRISPR/Cas9 validation in C. elegans\",\n      \"pmids\": [\"29593072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ELT-2 is a direct cleavage substrate not determined\", \"Effect size is modest and mechanism inferred rather than biochemical\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TASP1 loss to a human Mendelian disease, identifying active-site and loss-of-function variants and placing Taspase1 upstream of KMT2A/KMT2D activation, phenocopying Wiedemann-Steiner and Kabuki syndromes.\",\n      \"evidence\": \"Whole-exome sequencing with active-site missense (p.Thr234Met) and clinical phenotype comparison\",\n      \"pmids\": [\"31209944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical reconstitution of variant catalytic defects in this study\", \"Relative contribution of KMT2A vs KMT2D to the human phenotype not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the substrate repertoire beyond transcription to DNA damage tolerance, showing Taspase1 cleaves REV3L (Pol ζ catalytic subunit) to shield it from proteasomal degradation and sustain UV/cisplatin lesion responses.\",\n      \"evidence\": \"In vitro cleavage assay, endogenous knockin point mutations in HCT116, ubiquitination and DNA damage response assays\",\n      \"pmids\": [\"32064513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cleavage protects against ubiquitination mechanistically unclear\", \"In vivo relevance of REV3L cleavage not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Characterized the human disease at molecular resolution, showing TASP1 loss downregulates HOX genes, dysregulates TFIIA, and produces a distinct DNA methylation signature, with zebrafish KO reproducing cranial cartilage defects.\",\n      \"evidence\": \"Western blot, RNA-seq, proteomics and methylome of patient fibroblasts plus zebrafish CRISPR knockout\",\n      \"pmids\": [\"35512351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from TFIIA dysregulation to HOX downregulation not dissected\", \"Each omics arm is a single experiment\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added a cytoskeletal dimension by identifying the nucleo-cytoplasmic shuttle myosin Myo1f as a Taspase1 substrate whose cleavage antagonizes filopodia formation and migration.\",\n      \"evidence\": \"Co-IP/pulldown substrate identification, cleavage assays, live-cell filopodia imaging, and nuclear fractionation\",\n      \"pmids\": [\"35601920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation and structural cleavage site mapping limited\", \"Physiological significance of the macrophage/monocyte correlation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Taspase1 selects among its substrates in a given tissue, and what governs its substrate hierarchy beyond CKII priming of MLL1, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule for substrate prioritization across tissues\", \"Structural basis of cleavage-site recognition not described in the corpus\", \"Regulation of Taspase1 activity beyond HNF4alpha transcriptional control and CKII priming unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KMT2A\", \"KMT2D\", \"TFIIA\", \"REV3L\", \"MYO1F\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}