{"gene":"ATXN7L3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2008,"finding":"ATXN7L3 is a subunit of the deubiquitination (DUB) module within the TFTC/STAGA (GCN5 HAT-containing) complexes, and together with USP22 and ENY2, forms the module responsible for histone H2A and H2B deubiquitination activity. ATXN7L3 is required as a cofactor for full transcriptional activity by nuclear receptors.","method":"Biochemical purification of TFTC/STAGA complex, identification of subunits, functional assays for deubiquitinase activity, nuclear receptor coactivation assays, and Drosophila position effect variegation genetics","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex purification, functional deubiquitinase assay, genetic epistasis in Drosophila, nuclear receptor coactivation assays; replicated by multiple subsequent studies","pmids":["18206972"],"is_preprint":false},{"year":2011,"finding":"ATXN7L3 allosterically regulates USP22 through multiple interactions with different domains of other SAGA DUB module subunits (ATXN7, ATXN7L3, ENY2). Downregulation of ATXN7L3 by shRNA specifically inactivates SAGA deubiquitination activity, leading to a strong increase of global H2B ubiquitination, establishing SAGA as the major H2Bub deubiquitinase in human cells. SAGA DUB activity is required for full activation of SAGA-dependent inducible genes.","method":"shRNA knockdown of ATXN7L3, global H2Bub Western blot, chromatin immunoprecipitation at target gene loci, allosteric regulation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined molecular phenotype, ChIP, multiple orthogonal methods, independently replicated in subsequent studies","pmids":["21746879"],"is_preprint":false},{"year":2016,"finding":"Depletion of ATXN7L3 (a non-enzymatic component) increases global H2Bub1 levels, in contrast to USP22 depletion which decreases H2Bub1. ATXN7L3 and ENY2 coordinate activities of multiple H2B deubiquitinases: USP27X and USP51 (newly discovered DUBs) function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 binding. Thus, ATXN7L3 serves as a shared adaptor protein enabling activity of at least three distinct DUBs (USP22, USP27X, USP51).","method":"siRNA knockdown of ATXN7L3 vs USP22, global H2Bub1 Western blot, co-immunoprecipitation to identify USP27X and USP51 complexes with ATXN7L3/ENY2, tumor growth assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KD with defined molecular phenotype, multiple DUBs tested, functional tumor growth assays, rigorous controls","pmids":["27132940"],"is_preprint":false},{"year":2016,"finding":"ATXN7L3B (a paralog sharing 74% identity with the N-terminal region of ATXN7L3) competes with ATXN7L3 for ENY2 binding in vitro, and the resulting USP22-ATXN7L3B-ENY2 complex cannot efficiently deubiquitinate H2Bub1 in vitro. ATXN7L3B localizes to the cytoplasm, and its overexpression increases H2Bub1 levels (opposite to ATXN7L3 overexpression), establishing cytoplasmic ATXN7L3B as an indirect negative regulator of the SAGA DUB module through ENY2 competition.","method":"Co-immunoprecipitation, subcellular fractionation/immunofluorescence localization, in vitro deubiquitination assay, siRNA knockdown, H2Bub1 Western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of DUB assay with ATXN7L3B complex, competition binding, localization, and cellular overexpression/KD phenotypes; single lab but multiple orthogonal methods","pmids":["27601583"],"is_preprint":false},{"year":2017,"finding":"ATXN7L3 KD increases H2Bub1 levels and reduces cell migration in mammary epithelial and breast cancer cells. The anti-migratory effect of ATXN7L3 KD is abolished by simultaneous RNF20 KD, placing ATXN7L3 upstream of H2Bub1 in the regulation of cell migration.","method":"siRNA knockdown of ATXN7L3, H2Bub1 Western blot, cell migration assays, epistasis by double knockdown with RNF20","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double KD, defined phenotypic readout (migration), H2Bub1 measurement; single lab","pmids":["28604753"],"is_preprint":false},{"year":2021,"finding":"ATXN7L3 is essential for normal mouse embryonic development; Atxn7l3-/- embryos show developmental delay at E7.5 and die at mid-gestation. Loss of ATXN7L3 causes a strong increase in global H2Bub1 levels in null embryos and derived cell lines. Transcriptomic analysis of Atxn7l3-/- mESCs and MEFs shows that ATXN7L3-related DUB activity regulates only a subset of genes, and the strong H2Bub1 increase does not correlate with global changes in RNA Pol II occupancy or elongation.","method":"Mouse knockout (Atxn7l3-/-), embryo phenotyping, H2Bub1 Western blot, RNA-seq transcriptomics, ChIP for RNA Pol II","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with developmental phenotype, molecular characterization of H2Bub1 changes, genome-wide Pol II ChIP and RNA-seq; multiple orthogonal methods in single rigorous study","pmids":["33731875"],"is_preprint":false},{"year":2020,"finding":"ATXN7L3 functions as a coactivator for ERα-mediated transactivation in HCC cells, contributing to enhanced SMAD7 transcription. ATXN7L3 is recruited to the promoter regions of the SMAD7 gene and regulates histone H2B ubiquitination levels at that locus to enhance transcription.","method":"ChIP assay at SMAD7 promoter, shRNA knockdown, RT-qPCR, Western blot for H2Bub1, colony formation and xenograft tumor growth assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating recruitment to specific promoter, KD with defined gene expression and H2Bub1 phenotype; single lab, multiple methods","pmids":["33186807"],"is_preprint":false},{"year":2015,"finding":"ATXN7L3 associates with the adenovirus E1A transforming region protein complex via TRRAP, as part of a deubiquitinase complex containing USP22, ATXN7, and ATXN7L3.","method":"Co-immunoprecipitation of E1A-associated proteins, siRNA depletion of TRRAP to assess complex dependency","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, indirect context (viral protein complex), no direct functional assay for ATXN7L3 in this paper","pmids":["26559831"],"is_preprint":false},{"year":2022,"finding":"ATXN7L3-mediated DUB activity influences RNA Pol II elongation speed; deficient ATXN7L3-mediated DUB activity leads to increased elongation rates in non-irradiated and UV-irradiated cells. H2Bub levels in the 5' region of genes depend on intron-exon architecture and follow RNAPII local concentration and speed.","method":"ATXN7L3 knockdown, genome-wide H2Bub ChIP-seq, nascent RNA sequencing (GRO-seq/TT-seq), RNAPII ChIP-seq, computational analysis","journal":"Computational and structural biotechnology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with genome-wide mechanistic readouts (ChIP-seq, elongation rate measurement), single lab","pmids":["36659919"],"is_preprint":false},{"year":2024,"finding":"A recurrent heterozygous nonsense variant in ATXN7L3 [c.340C>T; p.(Arg114Ter)] reduces ATXN7L3 protein levels in patient fibroblasts and impairs deubiquitylation activity, as shown by increased histone H2Bub1 levels. This establishes ATXN7L3 loss-of-function variants as the cause of a syndromic neurodevelopmental disorder (developmental delay, hypotonia, distinctive facial features).","method":"Exome sequencing, Western blot for ATXN7L3 protein and H2Bub1 in patient fibroblasts, functional biochemical validation of DUB impairment","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells with protein level and H2Bub1 functional readout, genotype-phenotype established; single lab but direct biochemical evidence","pmids":["38753057"],"is_preprint":false},{"year":2024,"finding":"ATXN7L3-associated deubiquitinases mediate rapid deubiquitination of H2Bub1 in response to formaldehyde (FA) treatment, as a direct chromatin damage response independent of DNA damage signaling. This H2Bub1 loss was shown to be important for robust ATM/ATR signaling, efficient S-phase checkpoint, and suppression of micronuclei formation.","method":"FA treatment of human lung cells, Western blot for H2Bub1, shRNA/siRNA knockdown of ATXN7L3, DNA damage signaling assays (ATM/ATR), S-phase checkpoint assays, micronuclei quantification","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular and functional phenotypes, multiple readouts; single lab","pmids":["39254477"],"is_preprint":false},{"year":2025,"finding":"ATXN7L3 mediates TLR4/NF-κB signaling pathway regulation through histone H2B monoubiquitylation in trophoblasts; metformin corrects trophoblastic glycometabolic reprogramming and inflammation via ATXN7L3. ATXN7L3 was identified through proteomic screening and validated by ChIP and Co-IP assays at TLR4 promoter regions.","method":"Proteomic screening, ChIP assay, co-immunoprecipitation, ELISA, metabolic flux assays (oxidative phosphorylation/glycolysis), H2Bub1 measurement","journal":"Placenta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP and Co-IP with limited mechanistic follow-up, no mutagenesis or reconstitution","pmids":["40209519"],"is_preprint":false}],"current_model":"ATXN7L3 is a non-enzymatic adaptor subunit of the SAGA (and related) deubiquitination module (DUBm) that is essential for the catalytic activity of USP22 (and related DUBs USP27X and USP51) toward histone H2Bub1; it allosterically activates these USPs by bridging them to ENY2, coordinates the activity of multiple H2B deubiquitinases to regulate global H2Bub1 levels, is required for nuclear receptor and ERα coactivation at specific gene promoters, controls RNA Pol II elongation speed through H2Bub1 dynamics, is essential for mouse embryonic development, and its loss-of-function causes a syndromic neurodevelopmental disorder in humans."},"narrative":{"mechanistic_narrative":"ATXN7L3 is a non-enzymatic adaptor subunit of the SAGA/TFTC-STAGA deubiquitination module that is essential for histone H2B (and H2A) deubiquitination and for full transcriptional activation by nuclear receptors [PMID:18206972]. Within the module it functions as the obligate cofactor that activates the catalytic USP subunit: knockdown of ATXN7L3 inactivates SAGA DUB activity and drives a strong global increase in H2Bub1, establishing this module as the major H2Bub deubiquitinase in human cells, with activity controlled allosterically through ATXN7L3 contacts to other module subunits including ATXN7 and ENY2 [PMID:21746879]. ATXN7L3 acts as a shared adaptor for at least three distinct deubiquitinases—USP22, USP27X, and USP51—which compete for ATXN7L3/ENY2 binding, so ATXN7L3 coordinately sets global H2Bub1 levels rather than serving a single enzyme [PMID:27132940]. Through this control of H2Bub1, ATXN7L3 regulates a defined subset of genes by being recruited to specific promoters and modulating local H2B ubiquitination, contributing to ERα coactivation [PMID:33186807], cell migration upstream of RNF20-deposited H2Bub1 [PMID:28604753], and the dynamics of RNA Pol II transcriptional elongation [PMID:36659919]. ATXN7L3 is essential for mouse embryonic development, with null embryos dying at mid-gestation accompanied by strongly elevated H2Bub1 [PMID:33731875]. A recurrent heterozygous nonsense variant that reduces ATXN7L3 protein and impairs H2Bub1 deubiquitylation causes a syndromic neurodevelopmental disorder with developmental delay, hypotonia, and distinctive facial features [PMID:38753057].","teleology":[{"year":2008,"claim":"Established that ATXN7L3 is a constituent of the SAGA/TFTC-STAGA DUB module and links the module's deubiquitinase activity to nuclear receptor transcription, defining its place in chromatin-based gene regulation.","evidence":"Biochemical purification of TFTC/STAGA, DUB activity assays, nuclear receptor coactivation assays, and Drosophila PEV genetics","pmids":["18206972"],"confidence":"High","gaps":["Did not resolve whether ATXN7L3 contributes catalytically or only as a scaffold","Mechanism of how the module is targeted to specific promoters not defined"]},{"year":2011,"claim":"Showed ATXN7L3 is required for SAGA DUB catalysis, acting allosterically through inter-subunit contacts, and that the module is the dominant H2Bub deubiquitinase in human cells.","evidence":"shRNA knockdown, global H2Bub Western blot, ChIP at inducible target loci, allosteric interaction analysis","pmids":["21746879"],"confidence":"High","gaps":["Structural basis of allosteric activation not resolved","Which genes depend on this activity defined only at selected loci"]},{"year":2016,"claim":"Reframed ATXN7L3 from a single-complex subunit to a shared adaptor coordinating multiple H2B deubiquitinases, explaining why ATXN7L3 loss and USP22 loss have opposite effects on H2Bub1.","evidence":"Reciprocal siRNA of ATXN7L3 vs USP22, Co-IP identifying USP27X/USP51 complexes, H2Bub1 Western blot, tumor growth assays","pmids":["27132940"],"confidence":"High","gaps":["Relative contribution of each DUB to specific gene sets unclear","Determinants of partner selection among USP22/USP27X/USP51 not defined"]},{"year":2016,"claim":"Identified the cytoplasmic paralog ATXN7L3B as a negative regulator that competes for ENY2, revealing a sequestration mechanism that tunes module assembly and H2Bub1 levels.","evidence":"Co-IP, subcellular fractionation/IF, in vitro DUB assay, siRNA and overexpression with H2Bub1 readout","pmids":["27601583"],"confidence":"High","gaps":["Physiological conditions controlling ATXN7L3 vs ATXN7L3B balance unknown","Single lab"]},{"year":2017,"claim":"Placed ATXN7L3 functionally upstream of RNF20-deposited H2Bub1 in controlling cell migration, connecting its DUB activity to a cancer-relevant cellular phenotype.","evidence":"siRNA of ATXN7L3, double knockdown epistasis with RNF20, migration assays, H2Bub1 Western blot","pmids":["28604753"],"confidence":"Medium","gaps":["Direct gene targets driving migration not identified","Single lab"]},{"year":2020,"claim":"Demonstrated locus-specific coactivation, showing ATXN7L3 is recruited to the SMAD7 promoter and regulates H2Bub1 there to enhance ERα-driven transcription.","evidence":"ChIP at SMAD7 promoter, shRNA, RT-qPCR, H2Bub1 Western blot, colony formation and xenograft assays","pmids":["33186807"],"confidence":"Medium","gaps":["Mechanism of recruitment to the promoter not defined","Single lab; gene-specific"]},{"year":2021,"claim":"Established organismal essentiality and showed that despite a strong global H2Bub1 increase, ATXN7L3-dependent DUB activity regulates only a subset of genes without genome-wide Pol II changes.","evidence":"Atxn7l3-/- mouse knockout, embryo phenotyping, H2Bub1 Western blot, RNA-seq, Pol II ChIP","pmids":["33731875"],"confidence":"High","gaps":["Why only a subset of genes responds despite global H2Bub1 rise unexplained","Developmental pathways downstream of ATXN7L3 not mapped"]},{"year":2022,"claim":"Linked ATXN7L3 DUB activity to transcriptional elongation kinetics, showing deficient activity increases Pol II elongation speed in basal and UV-stressed conditions.","evidence":"ATXN7L3 knockdown, H2Bub ChIP-seq, nascent RNA sequencing, RNAPII ChIP-seq, computational analysis","pmids":["36659919"],"confidence":"Medium","gaps":["Causal direction between H2Bub dynamics and elongation not fully resolved","Single lab"]},{"year":2024,"claim":"Defined a chromatin damage response role, showing ATXN7L3-associated DUBs rapidly remove H2Bub1 after formaldehyde exposure to support ATM/ATR signaling and S-phase checkpoint integrity.","evidence":"Formaldehyde treatment of lung cells, ATXN7L3 knockdown, H2Bub1 Western blot, ATM/ATR and S-phase checkpoint assays, micronuclei quantification","pmids":["39254477"],"confidence":"Medium","gaps":["Which associated DUB executes the response unclear","Direct chromatin substrate dynamics not visualized"]},{"year":2024,"claim":"Connected ATXN7L3 loss-of-function to human disease, showing a recurrent nonsense variant reduces protein and impairs H2Bub1 deubiquitylation, causing a syndromic neurodevelopmental disorder.","evidence":"Exome sequencing, Western blot for ATXN7L3 and H2Bub1 in patient fibroblasts, biochemical DUB validation","pmids":["38753057"],"confidence":"Medium","gaps":["Neuronal mechanism linking H2Bub1 dysregulation to phenotype not established","Single recurrent variant; allelic series limited"]},{"year":2025,"claim":"Implicated ATXN7L3 in trophoblast TLR4/NF-κB regulation and metabolic-inflammatory reprogramming via H2B monoubiquitylation.","evidence":"Proteomic screening, ChIP and Co-IP at TLR4 promoter, ELISA, metabolic flux and H2Bub1 assays","pmids":["40209519"],"confidence":"Low","gaps":["No mutagenesis or reconstitution to confirm causality","Single lab; limited mechanistic follow-up"]},{"year":null,"claim":"How ATXN7L3 selects among partner DUBs and is targeted to specific promoters to regulate only a subset of genes, and how H2Bub1 dysregulation produces the neurodevelopmental phenotype, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ATXN7L3 in active vs inactive module states","Determinants of locus-specific recruitment unknown","Mechanistic link from H2Bub1 to organismal/neural phenotype unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":["SAGA/TFTC-STAGA deubiquitination module"],"partners":["USP22","ENY2","ATXN7","USP27X","USP51","ATXN7L3B","TRRAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14CW9","full_name":"Ataxin-7-like protein 3","aliases":["SAGA-associated factor 11 homolog"],"length_aa":347,"mass_kda":38.7,"function":"Component of the transcription regulatory histone acetylation (HAT) complex SAGA, a multiprotein complex that activates transcription by remodeling chromatin and mediating histone acetylation and deubiquitination. Within the SAGA complex, participates in a subcomplex that specifically deubiquitinates both histones H2A and H2B (PubMed:18206972, PubMed:21746879). The SAGA complex is recruited to specific gene promoters by activators such as MYC, where it is required for transcription. Required for nuclear receptor-mediated transactivation. Within the complex, it is required to recruit USP22 and ENY2 into the SAGA complex (PubMed:18206972). Regulates H2B monoubiquitination (H2Bub1) levels. Affects subcellular distribution of ENY2, USP22 and ATXN7L3B (PubMed:27601583)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14CW9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN7L3","classification":"Not Classified","n_dependent_lines":410,"n_total_lines":1208,"dependency_fraction":0.3394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":4.0},{"gene":"ENY2","stoichiometry":0.2},{"gene":"USP22","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATXN7L3","total_profiled":1310},"omim":[{"mim_id":"621377","title":"HAREL-TORA NEURODEVELOPMENTAL SYNDROME; HATONS","url":"https://www.omim.org/entry/621377"},{"mim_id":"619015","title":"ENY2 TRANSCRIPTION AND EXPORT COMPLEX 2 SUBUNIT; ENY2","url":"https://www.omim.org/entry/619015"},{"mim_id":"619010","title":"ATXN7-LIKE 3; ATXN7L3","url":"https://www.omim.org/entry/619010"},{"mim_id":"612116","title":"UBIQUITIN-SPECIFIC PROTEASE 22; USP22","url":"https://www.omim.org/entry/612116"},{"mim_id":"300984","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 105; XLID105","url":"https://www.omim.org/entry/300984"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN7L3"},"hgnc":{"alias_symbol":["DKFZp761G2113"],"prev_symbol":[]},"alphafold":{"accession":"Q14CW9","domains":[{"cath_id":"-","chopping":"12-60","consensus_level":"high","plddt":86.1778,"start":12,"end":60},{"cath_id":"-","chopping":"82-122","consensus_level":"high","plddt":82.991,"start":82,"end":122},{"cath_id":"-","chopping":"192-245","consensus_level":"high","plddt":84.7989,"start":192,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14CW9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14CW9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14CW9-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN7L3","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN7L3"},"sequence":{"accession":"Q14CW9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14CW9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14CW9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14CW9"}},"corpus_meta":[{"pmid":"18206972","id":"PMC_18206972","title":"A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencing.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18206972","citation_count":307,"is_preprint":false},{"pmid":"27132940","id":"PMC_27132940","title":"ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27132940","citation_count":122,"is_preprint":false},{"pmid":"21746879","id":"PMC_21746879","title":"The tightly controlled deubiquitination activity of the human SAGA complex differentially modifies distinct gene regulatory elements.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21746879","citation_count":114,"is_preprint":false},{"pmid":"31506425","id":"PMC_31506425","title":"High throughput circRNA sequencing analysis reveals novel insights into the mechanism of nitidine chloride against hepatocellular carcinoma.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31506425","citation_count":66,"is_preprint":false},{"pmid":"35192684","id":"PMC_35192684","title":"Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35192684","citation_count":43,"is_preprint":false},{"pmid":"31737900","id":"PMC_31737900","title":"Long non-coding RNA DSCAM-AS1 contributes to the tumorigenesis of cervical cancer by targeting miR-877-5p/ATXN7L3 axis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31737900","citation_count":43,"is_preprint":false},{"pmid":"35316324","id":"PMC_35316324","title":"Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35316324","citation_count":27,"is_preprint":false},{"pmid":"28604753","id":"PMC_28604753","title":"let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28604753","citation_count":26,"is_preprint":false},{"pmid":"37120350","id":"PMC_37120350","title":"Emerging molecular subtypes and therapies in acute lymphoblastic leukemia.","date":"2023","source":"Seminars in diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37120350","citation_count":24,"is_preprint":false},{"pmid":"33731875","id":"PMC_33731875","title":"Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33731875","citation_count":20,"is_preprint":false},{"pmid":"35806465","id":"PMC_35806465","title":"SAGA-Dependent Histone H2Bub1 Deubiquitination Is Essential for Cellular Ubiquitin Balance during Embryonic Development.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806465","citation_count":17,"is_preprint":false},{"pmid":"27601583","id":"PMC_27601583","title":"Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27601583","citation_count":13,"is_preprint":false},{"pmid":"33186807","id":"PMC_33186807","title":"ATXN7L3 positively regulates SMAD7 transcription in hepatocellular carcinoma with growth inhibitory function.","date":"2020","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33186807","citation_count":11,"is_preprint":false},{"pmid":"33090006","id":"PMC_33090006","title":"Identification of circ_0085616 as an Upregulated and Oncogenic Circular RNA in Cervical Cancer Via the miR-503-5p-Mediated ATXN7L3 Activation.","date":"2026","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/33090006","citation_count":10,"is_preprint":false},{"pmid":"26559831","id":"PMC_26559831","title":"The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26559831","citation_count":5,"is_preprint":false},{"pmid":"38753057","id":"PMC_38753057","title":"De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features.","date":"2024","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38753057","citation_count":3,"is_preprint":false},{"pmid":"39254477","id":"PMC_39254477","title":"Monoubiquitinated H2B, a Main Chromatin Target of Formaldehyde, Is Important for S-Phase Checkpoint Signaling and Genome Stability.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39254477","citation_count":3,"is_preprint":false},{"pmid":"36659919","id":"PMC_36659919","title":"Histone H2Bub dynamics in the 5' region of active genes are tightly linked to the UV-induced transcriptional response.","date":"2022","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/36659919","citation_count":2,"is_preprint":false},{"pmid":"40209519","id":"PMC_40209519","title":"Metformin ameliorates trophoblastic immunometabolic disorders via attenuating TLR4/NF-κB signaling through ATXN7L3-mediated histone H2B monoubiquitination.","date":"2025","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/40209519","citation_count":0,"is_preprint":false},{"pmid":"41760364","id":"PMC_41760364","title":"A Novel ATXN7L3 De Novo Variant Underlies Harel-Tora Neurodevelopmental Syndrome (HATONS) With Pre-Axial Polydactyly.","date":"2026","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41760364","citation_count":0,"is_preprint":false},{"pmid":"40667353","id":"PMC_40667353","title":"Long Noncoding RNAs Preserve Pancreatic Cancer Identity and Resist Cell Fate Conversion.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40667353","citation_count":0,"is_preprint":false},{"pmid":"41217722","id":"PMC_41217722","title":"The G→C rs590352 in the Protein-Coding Region of ATXN7L3B Gene Upregulates Its Expression In Vivo.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41217722","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14623,"output_tokens":3588,"usd":0.048844,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10984,"output_tokens":3869,"usd":0.075823,"stage2_stop_reason":"end_turn"},"total_usd":0.124667,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ATXN7L3 is a subunit of the deubiquitination (DUB) module within the TFTC/STAGA (GCN5 HAT-containing) complexes, and together with USP22 and ENY2, forms the module responsible for histone H2A and H2B deubiquitination activity. ATXN7L3 is required as a cofactor for full transcriptional activity by nuclear receptors.\",\n      \"method\": \"Biochemical purification of TFTC/STAGA complex, identification of subunits, functional assays for deubiquitinase activity, nuclear receptor coactivation assays, and Drosophila position effect variegation genetics\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex purification, functional deubiquitinase assay, genetic epistasis in Drosophila, nuclear receptor coactivation assays; replicated by multiple subsequent studies\",\n      \"pmids\": [\"18206972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN7L3 allosterically regulates USP22 through multiple interactions with different domains of other SAGA DUB module subunits (ATXN7, ATXN7L3, ENY2). Downregulation of ATXN7L3 by shRNA specifically inactivates SAGA deubiquitination activity, leading to a strong increase of global H2B ubiquitination, establishing SAGA as the major H2Bub deubiquitinase in human cells. SAGA DUB activity is required for full activation of SAGA-dependent inducible genes.\",\n      \"method\": \"shRNA knockdown of ATXN7L3, global H2Bub Western blot, chromatin immunoprecipitation at target gene loci, allosteric regulation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined molecular phenotype, ChIP, multiple orthogonal methods, independently replicated in subsequent studies\",\n      \"pmids\": [\"21746879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Depletion of ATXN7L3 (a non-enzymatic component) increases global H2Bub1 levels, in contrast to USP22 depletion which decreases H2Bub1. ATXN7L3 and ENY2 coordinate activities of multiple H2B deubiquitinases: USP27X and USP51 (newly discovered DUBs) function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 binding. Thus, ATXN7L3 serves as a shared adaptor protein enabling activity of at least three distinct DUBs (USP22, USP27X, USP51).\",\n      \"method\": \"siRNA knockdown of ATXN7L3 vs USP22, global H2Bub1 Western blot, co-immunoprecipitation to identify USP27X and USP51 complexes with ATXN7L3/ENY2, tumor growth assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KD with defined molecular phenotype, multiple DUBs tested, functional tumor growth assays, rigorous controls\",\n      \"pmids\": [\"27132940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATXN7L3B (a paralog sharing 74% identity with the N-terminal region of ATXN7L3) competes with ATXN7L3 for ENY2 binding in vitro, and the resulting USP22-ATXN7L3B-ENY2 complex cannot efficiently deubiquitinate H2Bub1 in vitro. ATXN7L3B localizes to the cytoplasm, and its overexpression increases H2Bub1 levels (opposite to ATXN7L3 overexpression), establishing cytoplasmic ATXN7L3B as an indirect negative regulator of the SAGA DUB module through ENY2 competition.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/immunofluorescence localization, in vitro deubiquitination assay, siRNA knockdown, H2Bub1 Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of DUB assay with ATXN7L3B complex, competition binding, localization, and cellular overexpression/KD phenotypes; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27601583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATXN7L3 KD increases H2Bub1 levels and reduces cell migration in mammary epithelial and breast cancer cells. The anti-migratory effect of ATXN7L3 KD is abolished by simultaneous RNF20 KD, placing ATXN7L3 upstream of H2Bub1 in the regulation of cell migration.\",\n      \"method\": \"siRNA knockdown of ATXN7L3, H2Bub1 Western blot, cell migration assays, epistasis by double knockdown with RNF20\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double KD, defined phenotypic readout (migration), H2Bub1 measurement; single lab\",\n      \"pmids\": [\"28604753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATXN7L3 is essential for normal mouse embryonic development; Atxn7l3-/- embryos show developmental delay at E7.5 and die at mid-gestation. Loss of ATXN7L3 causes a strong increase in global H2Bub1 levels in null embryos and derived cell lines. Transcriptomic analysis of Atxn7l3-/- mESCs and MEFs shows that ATXN7L3-related DUB activity regulates only a subset of genes, and the strong H2Bub1 increase does not correlate with global changes in RNA Pol II occupancy or elongation.\",\n      \"method\": \"Mouse knockout (Atxn7l3-/-), embryo phenotyping, H2Bub1 Western blot, RNA-seq transcriptomics, ChIP for RNA Pol II\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with developmental phenotype, molecular characterization of H2Bub1 changes, genome-wide Pol II ChIP and RNA-seq; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33731875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATXN7L3 functions as a coactivator for ERα-mediated transactivation in HCC cells, contributing to enhanced SMAD7 transcription. ATXN7L3 is recruited to the promoter regions of the SMAD7 gene and regulates histone H2B ubiquitination levels at that locus to enhance transcription.\",\n      \"method\": \"ChIP assay at SMAD7 promoter, shRNA knockdown, RT-qPCR, Western blot for H2Bub1, colony formation and xenograft tumor growth assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating recruitment to specific promoter, KD with defined gene expression and H2Bub1 phenotype; single lab, multiple methods\",\n      \"pmids\": [\"33186807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATXN7L3 associates with the adenovirus E1A transforming region protein complex via TRRAP, as part of a deubiquitinase complex containing USP22, ATXN7, and ATXN7L3.\",\n      \"method\": \"Co-immunoprecipitation of E1A-associated proteins, siRNA depletion of TRRAP to assess complex dependency\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, indirect context (viral protein complex), no direct functional assay for ATXN7L3 in this paper\",\n      \"pmids\": [\"26559831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATXN7L3-mediated DUB activity influences RNA Pol II elongation speed; deficient ATXN7L3-mediated DUB activity leads to increased elongation rates in non-irradiated and UV-irradiated cells. H2Bub levels in the 5' region of genes depend on intron-exon architecture and follow RNAPII local concentration and speed.\",\n      \"method\": \"ATXN7L3 knockdown, genome-wide H2Bub ChIP-seq, nascent RNA sequencing (GRO-seq/TT-seq), RNAPII ChIP-seq, computational analysis\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with genome-wide mechanistic readouts (ChIP-seq, elongation rate measurement), single lab\",\n      \"pmids\": [\"36659919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A recurrent heterozygous nonsense variant in ATXN7L3 [c.340C>T; p.(Arg114Ter)] reduces ATXN7L3 protein levels in patient fibroblasts and impairs deubiquitylation activity, as shown by increased histone H2Bub1 levels. This establishes ATXN7L3 loss-of-function variants as the cause of a syndromic neurodevelopmental disorder (developmental delay, hypotonia, distinctive facial features).\",\n      \"method\": \"Exome sequencing, Western blot for ATXN7L3 protein and H2Bub1 in patient fibroblasts, functional biochemical validation of DUB impairment\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells with protein level and H2Bub1 functional readout, genotype-phenotype established; single lab but direct biochemical evidence\",\n      \"pmids\": [\"38753057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATXN7L3-associated deubiquitinases mediate rapid deubiquitination of H2Bub1 in response to formaldehyde (FA) treatment, as a direct chromatin damage response independent of DNA damage signaling. This H2Bub1 loss was shown to be important for robust ATM/ATR signaling, efficient S-phase checkpoint, and suppression of micronuclei formation.\",\n      \"method\": \"FA treatment of human lung cells, Western blot for H2Bub1, shRNA/siRNA knockdown of ATXN7L3, DNA damage signaling assays (ATM/ATR), S-phase checkpoint assays, micronuclei quantification\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular and functional phenotypes, multiple readouts; single lab\",\n      \"pmids\": [\"39254477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATXN7L3 mediates TLR4/NF-κB signaling pathway regulation through histone H2B monoubiquitylation in trophoblasts; metformin corrects trophoblastic glycometabolic reprogramming and inflammation via ATXN7L3. ATXN7L3 was identified through proteomic screening and validated by ChIP and Co-IP assays at TLR4 promoter regions.\",\n      \"method\": \"Proteomic screening, ChIP assay, co-immunoprecipitation, ELISA, metabolic flux assays (oxidative phosphorylation/glycolysis), H2Bub1 measurement\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP and Co-IP with limited mechanistic follow-up, no mutagenesis or reconstitution\",\n      \"pmids\": [\"40209519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN7L3 is a non-enzymatic adaptor subunit of the SAGA (and related) deubiquitination module (DUBm) that is essential for the catalytic activity of USP22 (and related DUBs USP27X and USP51) toward histone H2Bub1; it allosterically activates these USPs by bridging them to ENY2, coordinates the activity of multiple H2B deubiquitinases to regulate global H2Bub1 levels, is required for nuclear receptor and ERα coactivation at specific gene promoters, controls RNA Pol II elongation speed through H2Bub1 dynamics, is essential for mouse embryonic development, and its loss-of-function causes a syndromic neurodevelopmental disorder in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN7L3 is a non-enzymatic adaptor subunit of the SAGA/TFTC-STAGA deubiquitination module that is essential for histone H2B (and H2A) deubiquitination and for full transcriptional activation by nuclear receptors [#0]. Within the module it functions as the obligate cofactor that activates the catalytic USP subunit: knockdown of ATXN7L3 inactivates SAGA DUB activity and drives a strong global increase in H2Bub1, establishing this module as the major H2Bub deubiquitinase in human cells, with activity controlled allosterically through ATXN7L3 contacts to other module subunits including ATXN7 and ENY2 [#1]. ATXN7L3 acts as a shared adaptor for at least three distinct deubiquitinases\\u2014USP22, USP27X, and USP51\\u2014which compete for ATXN7L3/ENY2 binding, so ATXN7L3 coordinately sets global H2Bub1 levels rather than serving a single enzyme [#2]. Through this control of H2Bub1, ATXN7L3 regulates a defined subset of genes by being recruited to specific promoters and modulating local H2B ubiquitination, contributing to ER\\u03b1 coactivation [#6], cell migration upstream of RNF20-deposited H2Bub1 [#4], and the dynamics of RNA Pol II transcriptional elongation [#8]. ATXN7L3 is essential for mouse embryonic development, with null embryos dying at mid-gestation accompanied by strongly elevated H2Bub1 [#5]. A recurrent heterozygous nonsense variant that reduces ATXN7L3 protein and impairs H2Bub1 deubiquitylation causes a syndromic neurodevelopmental disorder with developmental delay, hypotonia, and distinctive facial features [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that ATXN7L3 is a constituent of the SAGA/TFTC-STAGA DUB module and links the module's deubiquitinase activity to nuclear receptor transcription, defining its place in chromatin-based gene regulation.\",\n      \"evidence\": \"Biochemical purification of TFTC/STAGA, DUB activity assays, nuclear receptor coactivation assays, and Drosophila PEV genetics\",\n      \"pmids\": [\"18206972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether ATXN7L3 contributes catalytically or only as a scaffold\", \"Mechanism of how the module is targeted to specific promoters not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed ATXN7L3 is required for SAGA DUB catalysis, acting allosterically through inter-subunit contacts, and that the module is the dominant H2Bub deubiquitinase in human cells.\",\n      \"evidence\": \"shRNA knockdown, global H2Bub Western blot, ChIP at inducible target loci, allosteric interaction analysis\",\n      \"pmids\": [\"21746879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of allosteric activation not resolved\", \"Which genes depend on this activity defined only at selected loci\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reframed ATXN7L3 from a single-complex subunit to a shared adaptor coordinating multiple H2B deubiquitinases, explaining why ATXN7L3 loss and USP22 loss have opposite effects on H2Bub1.\",\n      \"evidence\": \"Reciprocal siRNA of ATXN7L3 vs USP22, Co-IP identifying USP27X/USP51 complexes, H2Bub1 Western blot, tumor growth assays\",\n      \"pmids\": [\"27132940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each DUB to specific gene sets unclear\", \"Determinants of partner selection among USP22/USP27X/USP51 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the cytoplasmic paralog ATXN7L3B as a negative regulator that competes for ENY2, revealing a sequestration mechanism that tunes module assembly and H2Bub1 levels.\",\n      \"evidence\": \"Co-IP, subcellular fractionation/IF, in vitro DUB assay, siRNA and overexpression with H2Bub1 readout\",\n      \"pmids\": [\"27601583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions controlling ATXN7L3 vs ATXN7L3B balance unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed ATXN7L3 functionally upstream of RNF20-deposited H2Bub1 in controlling cell migration, connecting its DUB activity to a cancer-relevant cellular phenotype.\",\n      \"evidence\": \"siRNA of ATXN7L3, double knockdown epistasis with RNF20, migration assays, H2Bub1 Western blot\",\n      \"pmids\": [\"28604753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct gene targets driving migration not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated locus-specific coactivation, showing ATXN7L3 is recruited to the SMAD7 promoter and regulates H2Bub1 there to enhance ER\\u03b1-driven transcription.\",\n      \"evidence\": \"ChIP at SMAD7 promoter, shRNA, RT-qPCR, H2Bub1 Western blot, colony formation and xenograft assays\",\n      \"pmids\": [\"33186807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of recruitment to the promoter not defined\", \"Single lab; gene-specific\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established organismal essentiality and showed that despite a strong global H2Bub1 increase, ATXN7L3-dependent DUB activity regulates only a subset of genes without genome-wide Pol II changes.\",\n      \"evidence\": \"Atxn7l3-/- mouse knockout, embryo phenotyping, H2Bub1 Western blot, RNA-seq, Pol II ChIP\",\n      \"pmids\": [\"33731875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only a subset of genes responds despite global H2Bub1 rise unexplained\", \"Developmental pathways downstream of ATXN7L3 not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked ATXN7L3 DUB activity to transcriptional elongation kinetics, showing deficient activity increases Pol II elongation speed in basal and UV-stressed conditions.\",\n      \"evidence\": \"ATXN7L3 knockdown, H2Bub ChIP-seq, nascent RNA sequencing, RNAPII ChIP-seq, computational analysis\",\n      \"pmids\": [\"36659919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between H2Bub dynamics and elongation not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a chromatin damage response role, showing ATXN7L3-associated DUBs rapidly remove H2Bub1 after formaldehyde exposure to support ATM/ATR signaling and S-phase checkpoint integrity.\",\n      \"evidence\": \"Formaldehyde treatment of lung cells, ATXN7L3 knockdown, H2Bub1 Western blot, ATM/ATR and S-phase checkpoint assays, micronuclei quantification\",\n      \"pmids\": [\"39254477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which associated DUB executes the response unclear\", \"Direct chromatin substrate dynamics not visualized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ATXN7L3 loss-of-function to human disease, showing a recurrent nonsense variant reduces protein and impairs H2Bub1 deubiquitylation, causing a syndromic neurodevelopmental disorder.\",\n      \"evidence\": \"Exome sequencing, Western blot for ATXN7L3 and H2Bub1 in patient fibroblasts, biochemical DUB validation\",\n      \"pmids\": [\"38753057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal mechanism linking H2Bub1 dysregulation to phenotype not established\", \"Single recurrent variant; allelic series limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ATXN7L3 in trophoblast TLR4/NF-\\u03baB regulation and metabolic-inflammatory reprogramming via H2B monoubiquitylation.\",\n      \"evidence\": \"Proteomic screening, ChIP and Co-IP at TLR4 promoter, ELISA, metabolic flux and H2Bub1 assays\",\n      \"pmids\": [\"40209519\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mutagenesis or reconstitution to confirm causality\", \"Single lab; limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATXN7L3 selects among partner DUBs and is targeted to specific promoters to regulate only a subset of genes, and how H2Bub1 dysregulation produces the neurodevelopmental phenotype, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ATXN7L3 in active vs inactive module states\", \"Determinants of locus-specific recruitment unknown\", \"Mechanistic link from H2Bub1 to organismal/neural phenotype unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"SAGA/TFTC-STAGA deubiquitination module\"],\n    \"partners\": [\"USP22\", \"ENY2\", \"ATXN7\", \"USP27X\", \"USP51\", \"ATXN7L3B\", \"TRRAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}