{"gene":"ATXN7L3B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2016,"finding":"ATXN7L3B interacts with ENY2 but not with other SAGA complex components; it localizes in the cytoplasm rather than the nucleus.","method":"Co-immunoprecipitation, subcellular fractionation/localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding demonstrated, localization by fractionation, single lab with multiple orthogonal methods","pmids":["27601583"],"is_preprint":false},{"year":2016,"finding":"In vitro, ATXN7L3B competes with ATXN7L3 for ENY2 binding; a reconstituted USP22-ATXN7L3B-ENY2 complex cannot efficiently deubiquitinate H2Bub1, in contrast to the ATXN7L3-containing DUB module.","method":"In vitro competition binding assay, in vitro deubiquitinase activity assay with reconstituted complexes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of complex and enzymatic assay, single lab with multiple orthogonal methods","pmids":["27601583"],"is_preprint":false},{"year":2016,"finding":"Overexpression of ATXN7L3B increases global H2Bub1 levels (opposite to ATXN7L3 overexpression which decreases H2Bub1), and knockdown of ATXN7L3B leads to concomitant loss of ENY2, indicating ATXN7L3B sequesters ENY2 in the cytoplasm to antagonize nuclear SAGA DUB activity.","method":"Overexpression and knockdown experiments with western blot for H2Bub1; ENY2 protein level measurement after ATXN7L3B knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean gain- and loss-of-function with specific molecular readout, single lab, multiple complementary experiments","pmids":["27601583"],"is_preprint":false},{"year":2016,"finding":"Knockdown of ATXN7L3B inhibits migration of breast cancer cells in vitro and limits expression of estrogen receptor (ER) target genes.","method":"siRNA knockdown, cell migration assay, gene expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotype, single lab, single method per readout","pmids":["27601583"],"is_preprint":false},{"year":2021,"finding":"ATXN7L3B promotes hepatocellular carcinoma (HCC) stemness (tumor-initiating ability), and metformin reduces ATXN7L3B levels in HCC cells, with metformin treatment decreasing ATXN7L3B-induced tumor-initiating ability in a HCC mouse model.","method":"Transcriptomic/proteomic analysis, knockdown/overexpression with tumor-initiating assays, in vivo HCC mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss/gain-of-function with in vivo model, single lab, limited mechanistic depth on pathway placement","pmids":["34375763"],"is_preprint":false},{"year":2025,"finding":"The synonymous SNP rs590352 G→C in exon 1 of ATXN7L3B disrupts binding sites for certain transcription factors (shown by EMSA), reduces reporter gene expression in luciferase assay, and results in lower allele-asymmetric in vivo ATXN7L3B expression for the C allele compared with the G allele.","method":"Electrophoretic mobility shift assay (EMSA), dual luciferase reporter assay, allele-asymmetric RNA-seq analysis","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, luciferase, in vivo expression), single lab","pmids":["41217722"],"is_preprint":false},{"year":2025,"finding":"CRISPRa-mediated upregulation of ATXN7L3B in adipose-derived stem cells significantly increases alkaline phosphatase activity and mineralization in monolayer and 3D culture, identifying ATXN7L3B as a novel osteogenic target.","method":"Genome-wide CRISPRa screen, alkaline phosphatase activity assay, mineralization assay in monolayer and 3D culture","journal":"Journal of tissue engineering","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional gain-of-function with specific cellular phenotype readout, single lab, single study","pmids":["41245170"],"is_preprint":false},{"year":2014,"finding":"lnc-SCA7 (ATXN7L3B locus; long noncoding RNA product) mediates post-transcriptional cross-talk with ATXN7 mRNA via miR-124, with STAGA required for miR-124 transcription initiation; mutations in ATXN7 disrupt this regulatory loop causing neuron-specific increases in ATXN7 expression.","method":"RNA interaction studies, miRNA reporter assays, mouse models of SCA7","journal":"Nature structural & molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — this finding concerns the lncRNA product of the locus (lnc-SCA7), not the ATXN7L3B protein; included with low confidence as mechanistically informative about the locus but not the canonical protein","pmids":["25306109"],"is_preprint":false}],"current_model":"ATXN7L3B is a cytoplasmic protein that shares 74% identity with the N-terminal region of ATXN7L3; it binds ENY2 and sequesters it away from the nucleus, thereby competing with ATXN7L3 for ENY2 binding, preventing formation of a functional SAGA DUB module, and raising global H2Bub1 levels—functioning as a dominant-negative regulator of SAGA deubiquitinase activity that also influences ER target gene expression, breast cancer cell migration, HCC stemness, and (when upregulated) osteogenic differentiation."},"narrative":{"mechanistic_narrative":"ATXN7L3B is a cytoplasmic protein that acts as a dominant-negative regulator of the SAGA deubiquitinase (DUB) module by sequestering the shared co-factor ENY2 away from the nucleus [PMID:27601583]. It binds ENY2 but none of the other SAGA components, and in vitro it competes directly with ATXN7L3 for ENY2; a reconstituted USP22-ATXN7L3B-ENY2 complex is catalytically deficient and cannot efficiently deubiquitinate H2Bub1, unlike the ATXN7L3-containing module [PMID:27601583]. Consistent with this antagonism, overexpression of ATXN7L3B raises global H2Bub1 levels while its knockdown destabilizes ENY2 [PMID:27601583]. Through this regulatory role ATXN7L3B influences estrogen receptor target gene expression and breast cancer cell migration [PMID:27601583] and promotes hepatocellular carcinoma stemness, an activity reduced by metformin [PMID:34375763]. Its upregulation also drives osteogenic differentiation of adipose-derived stem cells [PMID:41245170], and a synonymous promoter-proximal SNP (rs590352) modulates its allele-asymmetric expression by disrupting transcription factor binding [PMID:41217722].","teleology":[{"year":2014,"claim":"Before the protein was characterized, the question was whether the ATXN7L3B locus had any regulatory output; the lncRNA product lnc-SCA7 was found to engage in post-transcriptional cross-talk with ATXN7 mRNA via miR-124, establishing the locus as part of a SCA7-relevant regulatory loop.","evidence":"RNA interaction studies, miRNA reporter assays, and SCA7 mouse models","pmids":["25306109"],"confidence":"Low","gaps":["This finding concerns the lncRNA product of the locus, not the ATXN7L3B protein","Does not address ATXN7L3B protein function or its relationship to SAGA","Mechanistic link between the lncRNA loop and protein-level activity is unestablished"]},{"year":2016,"claim":"The central question of what ATXN7L3B does at the molecular level was answered by showing it binds ENY2 (but no other SAGA subunit), localizes to the cytoplasm, and competes with ATXN7L3 for ENY2 to form a catalytically dead DUB module that fails to remove H2Bub1.","evidence":"Co-IP, subcellular fractionation, in vitro competition binding, and reconstituted in vitro deubiquitinase assays with USP22/ATXN7L3/ENY2","pmids":["27601583"],"confidence":"High","gaps":["Structural basis of ATXN7L3B-ENY2 binding and how it excludes USP22 activity is not resolved","Whether ENY2 sequestration occurs constitutively or is regulated by signaling is unknown","No cell-type-resolved measurement of the in vivo ATXN7L3B:ATXN7L3 ratio governing H2Bub1"]},{"year":2016,"claim":"Cellular gain- and loss-of-function established that ATXN7L3B antagonism of SAGA DUB activity has functional consequences, raising global H2Bub1 and supporting ER target gene expression and breast cancer cell migration.","evidence":"Overexpression/knockdown with H2Bub1 and ENY2 western blots; siRNA knockdown with migration assays and ER target gene expression analysis","pmids":["27601583"],"confidence":"Medium","gaps":["Direct demonstration that migration and ER gene effects require H2Bub1/ENY2 sequestration (vs an independent activity) is incomplete","Single method per phenotypic readout","No genome-wide map of H2Bub1 changes driven by ATXN7L3B"]},{"year":2021,"claim":"Extending its oncogenic relevance, ATXN7L3B was shown to promote hepatocellular carcinoma tumor-initiating capacity and to be a metformin-responsive target, linking it to cancer stemness.","evidence":"Transcriptomic/proteomic profiling, knockdown/overexpression with tumor-initiating assays, and an in vivo HCC mouse model with metformin treatment","pmids":["34375763"],"confidence":"Medium","gaps":["Whether HCC stemness depends on the ENY2/H2Bub1 axis or a separate mechanism is unresolved","How metformin lowers ATXN7L3B levels is not defined","Limited mechanistic pathway placement"]},{"year":2025,"claim":"The regulation and broader physiological role of ATXN7L3B were probed, showing a synonymous SNP controls its allele-specific expression via transcription factor binding, and that its upregulation drives osteogenic differentiation.","evidence":"EMSA, dual luciferase reporter, and allele-asymmetric RNA-seq for rs590352; genome-wide CRISPRa screen with alkaline phosphatase and mineralization assays in adipose-derived stem cells","pmids":["41217722","41245170"],"confidence":"Medium","gaps":["The transcription factors bound at rs590352 are not identified","Whether the osteogenic effect operates through ENY2/H2Bub1 regulation is unknown","Single-study, single-lab findings for each phenotype"]},{"year":null,"claim":"It remains unresolved how the cytoplasmic ATXN7L3B-ENY2 sequestration mechanism is wired to its diverse downstream phenotypes (ER signaling, HCC stemness, osteogenesis) and whether these all converge on global H2Bub1 control.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ATXN7L3B-ENY2 interface","No causal chain linking H2Bub1 changes to specific differentiation or cancer outcomes","Regulatory inputs controlling ATXN7L3B abundance are largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["ENY2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96GX2","full_name":"Ataxin-7-like protein 3B","aliases":[],"length_aa":97,"mass_kda":10.8,"function":"By binding to ENY2, interferes with the nuclear functions of the deubiquitinase (DUB) module of the SAGA complex which consists of ENY2, ATXN7, ATXN7L3 and the histone deubiquitinating component USP22. Affects USP22 DUB activity toward histones indirectly by changing the subcellular distribution of ENY2 and altering ENY2 availability for ATXN7L3 interaction. Regulates H2B monoubiquitination (H2Bub1) levels through cytoplasmic sequestration of ENY2 resulting in loss of nuclear ENY2-ATXN7L3 association which destabilizes ATXN7L3. Affects protein expression levels of ENY2 and ATXN7L3","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96GX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN7L3B","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ENY2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATXN7L3B","total_profiled":1310},"omim":[{"mim_id":"615579","title":"ATAXIN 7-LIKE 3B; ATXN7L3B","url":"https://www.omim.org/entry/615579"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN7L3B"},"hgnc":{"alias_symbol":["lnc-SCA7"],"prev_symbol":[]},"alphafold":{"accession":"Q96GX2","domains":[{"cath_id":"1.20.5","chopping":"8-42","consensus_level":"high","plddt":93.756,"start":8,"end":42}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GX2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GX2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GX2-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN7L3B","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN7L3B"},"sequence":{"accession":"Q96GX2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GX2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GX2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GX2"}},"corpus_meta":[{"pmid":"25306109","id":"PMC_25306109","title":"Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7.","date":"2014","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25306109","citation_count":76,"is_preprint":false},{"pmid":"30886212","id":"PMC_30886212","title":"Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination.","date":"2019","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30886212","citation_count":22,"is_preprint":false},{"pmid":"23475819","id":"PMC_23475819","title":"Deletion of chromosome 12q21 affecting KCNC2 and ATXN7L3B in a family with neurodevelopmental delay and ataxia.","date":"2013","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23475819","citation_count":18,"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":"34375763","id":"PMC_34375763","title":"ATXN7L3B promotes hepatocellular carcinoma stemness and is downregulated by metformin.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34375763","citation_count":7,"is_preprint":false},{"pmid":"29168350","id":"PMC_29168350","title":"Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes.","date":"2017","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29168350","citation_count":7,"is_preprint":false},{"pmid":"31797724","id":"PMC_31797724","title":"Potential regulatory SNPs in the ATXN7L3B and KRT15 genes are associated with gender-specific colorectal cancer risk.","date":"2019","source":"Personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31797724","citation_count":6,"is_preprint":false},{"pmid":"41245170","id":"PMC_41245170","title":"CRISPRa genome-wide screen identifies novel gene targets for osteogenic cell engineering.","date":"2025","source":"Journal of tissue engineering","url":"https://pubmed.ncbi.nlm.nih.gov/41245170","citation_count":2,"is_preprint":false},{"pmid":"40653076","id":"PMC_40653076","title":"Ursodeoxycholic acid alleviates multiple sclerosis via TGR5-dependent microglial regulation in mice.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40653076","citation_count":2,"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":6668,"output_tokens":1869,"usd":0.024019,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8692,"output_tokens":2484,"usd":0.05278,"stage2_stop_reason":"end_turn"},"total_usd":0.076799,"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\": 2016,\n      \"finding\": \"ATXN7L3B interacts with ENY2 but not with other SAGA complex components; it localizes in the cytoplasm rather than the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding demonstrated, localization by fractionation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27601583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vitro, ATXN7L3B competes with ATXN7L3 for ENY2 binding; a reconstituted USP22-ATXN7L3B-ENY2 complex cannot efficiently deubiquitinate H2Bub1, in contrast to the ATXN7L3-containing DUB module.\",\n      \"method\": \"In vitro competition binding assay, in vitro deubiquitinase activity assay with reconstituted complexes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of complex and enzymatic assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27601583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of ATXN7L3B increases global H2Bub1 levels (opposite to ATXN7L3 overexpression which decreases H2Bub1), and knockdown of ATXN7L3B leads to concomitant loss of ENY2, indicating ATXN7L3B sequesters ENY2 in the cytoplasm to antagonize nuclear SAGA DUB activity.\",\n      \"method\": \"Overexpression and knockdown experiments with western blot for H2Bub1; ENY2 protein level measurement after ATXN7L3B knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain- and loss-of-function with specific molecular readout, single lab, multiple complementary experiments\",\n      \"pmids\": [\"27601583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of ATXN7L3B inhibits migration of breast cancer cells in vitro and limits expression of estrogen receptor (ER) target genes.\",\n      \"method\": \"siRNA knockdown, cell migration assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotype, single lab, single method per readout\",\n      \"pmids\": [\"27601583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATXN7L3B promotes hepatocellular carcinoma (HCC) stemness (tumor-initiating ability), and metformin reduces ATXN7L3B levels in HCC cells, with metformin treatment decreasing ATXN7L3B-induced tumor-initiating ability in a HCC mouse model.\",\n      \"method\": \"Transcriptomic/proteomic analysis, knockdown/overexpression with tumor-initiating assays, in vivo HCC mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss/gain-of-function with in vivo model, single lab, limited mechanistic depth on pathway placement\",\n      \"pmids\": [\"34375763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The synonymous SNP rs590352 G→C in exon 1 of ATXN7L3B disrupts binding sites for certain transcription factors (shown by EMSA), reduces reporter gene expression in luciferase assay, and results in lower allele-asymmetric in vivo ATXN7L3B expression for the C allele compared with the G allele.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), dual luciferase reporter assay, allele-asymmetric RNA-seq analysis\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, luciferase, in vivo expression), single lab\",\n      \"pmids\": [\"41217722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPRa-mediated upregulation of ATXN7L3B in adipose-derived stem cells significantly increases alkaline phosphatase activity and mineralization in monolayer and 3D culture, identifying ATXN7L3B as a novel osteogenic target.\",\n      \"method\": \"Genome-wide CRISPRa screen, alkaline phosphatase activity assay, mineralization assay in monolayer and 3D culture\",\n      \"journal\": \"Journal of tissue engineering\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional gain-of-function with specific cellular phenotype readout, single lab, single study\",\n      \"pmids\": [\"41245170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"lnc-SCA7 (ATXN7L3B locus; long noncoding RNA product) mediates post-transcriptional cross-talk with ATXN7 mRNA via miR-124, with STAGA required for miR-124 transcription initiation; mutations in ATXN7 disrupt this regulatory loop causing neuron-specific increases in ATXN7 expression.\",\n      \"method\": \"RNA interaction studies, miRNA reporter assays, mouse models of SCA7\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — this finding concerns the lncRNA product of the locus (lnc-SCA7), not the ATXN7L3B protein; included with low confidence as mechanistically informative about the locus but not the canonical protein\",\n      \"pmids\": [\"25306109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN7L3B is a cytoplasmic protein that shares 74% identity with the N-terminal region of ATXN7L3; it binds ENY2 and sequesters it away from the nucleus, thereby competing with ATXN7L3 for ENY2 binding, preventing formation of a functional SAGA DUB module, and raising global H2Bub1 levels—functioning as a dominant-negative regulator of SAGA deubiquitinase activity that also influences ER target gene expression, breast cancer cell migration, HCC stemness, and (when upregulated) osteogenic differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN7L3B is a cytoplasmic protein that acts as a dominant-negative regulator of the SAGA deubiquitinase (DUB) module by sequestering the shared co-factor ENY2 away from the nucleus [#0, #2]. It binds ENY2 but none of the other SAGA components, and in vitro it competes directly with ATXN7L3 for ENY2; a reconstituted USP22-ATXN7L3B-ENY2 complex is catalytically deficient and cannot efficiently deubiquitinate H2Bub1, unlike the ATXN7L3-containing module [#0, #1]. Consistent with this antagonism, overexpression of ATXN7L3B raises global H2Bub1 levels while its knockdown destabilizes ENY2 [#2]. Through this regulatory role ATXN7L3B influences estrogen receptor target gene expression and breast cancer cell migration [#3] and promotes hepatocellular carcinoma stemness, an activity reduced by metformin [#4]. Its upregulation also drives osteogenic differentiation of adipose-derived stem cells [#6], and a synonymous promoter-proximal SNP (rs590352) modulates its allele-asymmetric expression by disrupting transcription factor binding [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before the protein was characterized, the question was whether the ATXN7L3B locus had any regulatory output; the lncRNA product lnc-SCA7 was found to engage in post-transcriptional cross-talk with ATXN7 mRNA via miR-124, establishing the locus as part of a SCA7-relevant regulatory loop.\",\n      \"evidence\": \"RNA interaction studies, miRNA reporter assays, and SCA7 mouse models\",\n      \"pmids\": [\"25306109\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"This finding concerns the lncRNA product of the locus, not the ATXN7L3B protein\",\n        \"Does not address ATXN7L3B protein function or its relationship to SAGA\",\n        \"Mechanistic link between the lncRNA loop and protein-level activity is unestablished\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The central question of what ATXN7L3B does at the molecular level was answered by showing it binds ENY2 (but no other SAGA subunit), localizes to the cytoplasm, and competes with ATXN7L3 for ENY2 to form a catalytically dead DUB module that fails to remove H2Bub1.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, in vitro competition binding, and reconstituted in vitro deubiquitinase assays with USP22/ATXN7L3/ENY2\",\n      \"pmids\": [\"27601583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of ATXN7L3B-ENY2 binding and how it excludes USP22 activity is not resolved\",\n        \"Whether ENY2 sequestration occurs constitutively or is regulated by signaling is unknown\",\n        \"No cell-type-resolved measurement of the in vivo ATXN7L3B:ATXN7L3 ratio governing H2Bub1\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cellular gain- and loss-of-function established that ATXN7L3B antagonism of SAGA DUB activity has functional consequences, raising global H2Bub1 and supporting ER target gene expression and breast cancer cell migration.\",\n      \"evidence\": \"Overexpression/knockdown with H2Bub1 and ENY2 western blots; siRNA knockdown with migration assays and ER target gene expression analysis\",\n      \"pmids\": [\"27601583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct demonstration that migration and ER gene effects require H2Bub1/ENY2 sequestration (vs an independent activity) is incomplete\",\n        \"Single method per phenotypic readout\",\n        \"No genome-wide map of H2Bub1 changes driven by ATXN7L3B\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending its oncogenic relevance, ATXN7L3B was shown to promote hepatocellular carcinoma tumor-initiating capacity and to be a metformin-responsive target, linking it to cancer stemness.\",\n      \"evidence\": \"Transcriptomic/proteomic profiling, knockdown/overexpression with tumor-initiating assays, and an in vivo HCC mouse model with metformin treatment\",\n      \"pmids\": [\"34375763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether HCC stemness depends on the ENY2/H2Bub1 axis or a separate mechanism is unresolved\",\n        \"How metformin lowers ATXN7L3B levels is not defined\",\n        \"Limited mechanistic pathway placement\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The regulation and broader physiological role of ATXN7L3B were probed, showing a synonymous SNP controls its allele-specific expression via transcription factor binding, and that its upregulation drives osteogenic differentiation.\",\n      \"evidence\": \"EMSA, dual luciferase reporter, and allele-asymmetric RNA-seq for rs590352; genome-wide CRISPRa screen with alkaline phosphatase and mineralization assays in adipose-derived stem cells\",\n      \"pmids\": [\"41217722\", \"41245170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The transcription factors bound at rs590352 are not identified\",\n        \"Whether the osteogenic effect operates through ENY2/H2Bub1 regulation is unknown\",\n        \"Single-study, single-lab findings for each phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the cytoplasmic ATXN7L3B-ENY2 sequestration mechanism is wired to its diverse downstream phenotypes (ER signaling, HCC stemness, osteogenesis) and whether these all converge on global H2Bub1 control.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the ATXN7L3B-ENY2 interface\",\n        \"No causal chain linking H2Bub1 changes to specific differentiation or cancer outcomes\",\n        \"Regulatory inputs controlling ATXN7L3B abundance are largely uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ENY2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}