{"gene":"ATXN1L","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2007,"finding":"ATXN1L (BOAT) competes with polyglutamine-expanded ATXN1 for incorporation into the native CIC-containing complex; elevated ATXN1L levels displace mutant ATXN1 from this complex, suppressing SCA1 neuropathology in knock-in mice.","method":"Targeted duplication of mouse Atxn1l locus; genetic epistasis in SCA1 knock-in mouse model; co-immunoprecipitation demonstrating displacement of mutant ATXN1 from CIC complex","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis in vivo with multiple readouts, replicated across labs subsequently","pmids":["17322884"],"is_preprint":false},{"year":2011,"finding":"ATXN1L forms a complex with the transcriptional repressor CIC and stabilizes CIC protein; loss of ATXN1L destabilizes CIC, derepresses Etv4, and thereby activates Mmp gene expression (including MMP9), causing defects in extracellular matrix remodeling and lung alveolarization.","method":"Atxn1L knockout mice; Atxn1-/-;Atxn1L-/- double knockout mice; gene expression analysis; genetic epistasis with Cic-deficient mice","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined molecular and developmental phenotype, genetic epistasis, replicated in double-KO","pmids":["22014525"],"is_preprint":false},{"year":2011,"finding":"ATXN1L (BOAT1) and ATXN1 are components of the Notch signalling pathway; both proteins bind to the promoter region of Hey1 and inhibit Notch transcriptional output through direct interactions with CBF1.","method":"Drosophila BOAT1 functional analysis; ChIP showing binding to Hey1 promoter; co-immunoprecipitation with CBF1 in mammalian cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and Co-IP with functional validation in two systems, single lab","pmids":["21475249"],"is_preprint":false},{"year":2017,"finding":"ATXN1L deletion reduces CIC protein levels, leading to de-repression of ETS transcription factors ETV1, ETV4, and ETV5 and promoting resistance to MEK/RAF inhibitors; the ATXN1L-CIC-ETS axis modulates sensitivity to MAPK pathway inhibition.","method":"Genome-scale CRISPR-Cas9 loss-of-function screens; ATXN1L deletion validated in cancer cell lines; ectopic ETV1/4/5 expression phenocopying ATXN1L loss","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genome-scale CRISPR screen with orthogonal genetic validation across multiple cell lines","pmids":["28178529"],"is_preprint":false},{"year":2013,"finding":"ATXN1L regulates hematopoietic stem cell (HSC) quiescence; Atxn1L-null mice have greater numbers of HSCs with higher proliferation rates and gene expression changes consistent with reduced quiescence.","method":"Atxn1L knockout mice; in vitro and in vivo HSC functional assays; molecular gene expression analyses","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and molecular characterization, single lab","pmids":["23555280"],"is_preprint":false},{"year":2018,"finding":"ATXN1L and CIC have a reciprocal functional relationship: loss of either affects target gene regulation; the CIC-ATXN1-ATXN1L axis regulates cell cycle and mitotic division gene programs.","method":"ATXN1LKO and CICKO human cell lines; transcriptomic analysis; functional in vitro studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal KO cell lines with transcriptomic readout, single lab","pmids":["30093628"],"is_preprint":false},{"year":2020,"finding":"Loss of ATXN1L leads to polyubiquitination and proteasomal degradation of CIC protein, mediated by the E3 ubiquitin ligase TRIM25, independently of ERK activity.","method":"ATXN1LKO human cell lines; proteasome inhibitor assays; TRIM25 knockdown/overexpression; ubiquitination assays; validation in glioma-derived cell lines","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, ubiquitination assay, TRIM25 KD, inhibitor treatment) in multiple cell systems, single lab","pmids":["33115448"],"is_preprint":false},{"year":2022,"finding":"miR-136-5p targets ATXN1L; ATXN1L binds CIC to suppress PYDC1 expression, thereby promoting pyroptosis in cardiomyocytes; miR-136-5p suppresses pyroptosis by inhibiting ATXN1L/CIC binding.","method":"Dual-luciferase reporter assay (miR-136-5p targeting ATXN1L); co-immunoprecipitation (ATXN1L-CIC interaction); cell transfection with ATXN1L overexpression/knockdown; LPS-induced pyroptosis model","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and reporter assay in a single lab, novel cardiomyocyte context without independent replication","pmids":["35084609"],"is_preprint":false},{"year":2022,"finding":"ATXN1L promotes deacetylation of histone H3 through recruitment of HDAC3 to the NOL3 promoter, thereby inhibiting NOL3 expression and promoting cardiomyocyte apoptosis and pyroptosis.","method":"ChIP (ATXN1L and HDAC3 binding to NOL3 promoter); ATXN1L knockout adenovirus in rats; HDAC3 inhibition; immunofluorescence for HDAC3 localization; immunoprecipitation for HDAC3-H3 binding","journal":"Journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — ChIP and Co-IP in a single lab; novel mechanism not independently replicated","pmids":["35414011"],"is_preprint":false},{"year":2024,"finding":"The CIC-ATXN1L complex represses Notch signaling in marginal zone B cells by suppressing ETV4; ATXN1L deficiency specifically de-represses ETV4, which inhibits Notch1 and Notch2 transcription and thereby impairs marginal zone B cell development.","method":"B cell-specific Atxn1l conditional knockout mice (Atxn1lf/f;Cd19-Cre); Etv4-deletion epistasis; flow cytometry; Notch signaling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with genetic epistasis (Etv4-deletion rescue), defined cellular phenotype, multiple in vivo readouts","pmids":["39632849"],"is_preprint":false},{"year":2025,"finding":"The CIC-ATXN1L transcriptional repressor complex binds an 8-nucleotide motif near interferon (IFN) and IFN-stimulated gene (ISG) promoters and prevents their basal expression; MAPK pathway activation during viral infection triggers rapid degradation of the CIC-ATXN1L complex, relieving repression and allowing IFN/ISG induction.","method":"DNA-binding assays identifying 8-nt motif; CRISPR KO of CIC and ATXN1L in human and mouse cells; viral infection models; MAPK activation studies; ChIP for complex binding at IFN/ISG promoters","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, KO, motif binding, viral infection), validated in both human and mouse systems","pmids":["40132591"],"is_preprint":false},{"year":2025,"finding":"CIC short isoform (CIC-S) preferentially interacts with ATXN1L, while CIC long isoform (CIC-L) preferentially interacts with ATXN1; loss of CIC-S causes perinatal lethality phenocopying ATXN1L knockout, whereas loss of CIC-L causes cognitive deficits phenocopying ATXN1 knockout, demonstrating isoform-specific paralog interactions.","method":"Mouse knockin models expressing only CIC-L or CIC-S; co-immunoprecipitation showing isoform-selective interactions with ATXN1 vs ATXN1L; behavioral and developmental phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with isoform-specific knockin mice and phenotypic validation; preprint not yet peer-reviewed","pmids":["41279815"],"is_preprint":true}],"current_model":"ATXN1L functions primarily as a binding partner and stabilizer of the transcriptional repressor CIC, forming a complex that suppresses ETS transcription factors (ETV1/4/5), Notch target genes, and interferon/ISG promoters; when ATXN1L is lost, the E3 ubiquitin ligase TRIM25 polyubiquitinates CIC for proteasomal degradation, de-repressing downstream targets and modulating MAPK pathway sensitivity, ECM remodeling, B cell development, HSC quiescence, and antiviral innate immunity."},"narrative":{"teleology":[{"year":2007,"claim":"Whether ATXN1L participates in the same complex as ATXN1 was unknown; demonstrating that ATXN1L competes with mutant ATXN1 for the native CIC-containing complex established it as a functional paralog and potential modifier of SCA1 disease.","evidence":"Targeted duplication of mouse Atxn1l locus plus co-immunoprecipitation in SCA1 knock-in mice showing displacement of mutant ATXN1","pmids":["17322884"],"confidence":"High","gaps":["Structural basis for competitive binding not determined","Whether ATXN1L and ATXN1 have non-overlapping functions beyond CIC complex occupancy was unclear"]},{"year":2011,"claim":"The molecular consequence of ATXN1L loss was unknown; knockout studies revealed that ATXN1L stabilizes CIC protein and that its absence de-represses ETV4/MMP targets causing lung alveolarization defects, establishing the ATXN1L–CIC–ETS axis as a physiological regulatory module.","evidence":"Atxn1L single and Atxn1/Atxn1L double knockout mice with gene expression and developmental phenotyping; ChIP and co-IP showing ATXN1L binding at Notch target (Hey1) promoters with CBF1","pmids":["22014525","21475249"],"confidence":"High","gaps":["Mechanism by which ATXN1L stabilizes CIC protein was not identified","Whether Notch regulation via CBF1 is CIC-dependent or represents an independent ATXN1L function was unresolved"]},{"year":2013,"claim":"Whether ATXN1L regulates stem cell biology was untested; Atxn1L-null mice showed expanded, hyperproliferative HSCs, linking the CIC-stabilizing function to maintenance of hematopoietic stem cell quiescence.","evidence":"Atxn1L knockout mice with in vivo and in vitro HSC assays and molecular profiling","pmids":["23555280"],"confidence":"Medium","gaps":["Whether HSC phenotype is CIC-dependent was not formally tested with epistasis","Downstream gene programs driving quiescence loss were not fully defined"]},{"year":2017,"claim":"Whether the ATXN1L–CIC axis has therapeutic relevance was unknown; genome-scale CRISPR screens identified ATXN1L loss as a driver of resistance to MEK/RAF inhibitors through de-repression of ETV1/4/5, connecting this complex to MAPK pathway drug sensitivity in cancer.","evidence":"Genome-scale CRISPR-Cas9 screens in cancer cell lines; ectopic ETV expression phenocopying ATXN1L loss","pmids":["28178529"],"confidence":"High","gaps":["Whether restoring ATXN1L or CIC can re-sensitize resistant tumors was not tested","Relative contribution of individual ETV factors to resistance was not resolved"]},{"year":2020,"claim":"The biochemical mechanism by which CIC is destabilized upon ATXN1L loss was unknown; identification of TRIM25 as the E3 ligase that polyubiquitinates CIC for proteasomal degradation — independently of ERK activity — provided the missing proteolytic link.","evidence":"ATXN1L-KO human cell lines with proteasome inhibitor treatment, ubiquitination assays, and TRIM25 knockdown/overexpression across multiple cell systems","pmids":["33115448"],"confidence":"High","gaps":["How ATXN1L physically shields CIC from TRIM25 access is unknown","Whether additional E3 ligases contribute in other tissues was not explored"]},{"year":2024,"claim":"Whether the ATXN1L–CIC–ETV4 axis operates in immune cell development was untested; conditional B cell-specific knockout demonstrated that ATXN1L deficiency de-represses ETV4, which in turn suppresses Notch1/2 transcription and impairs marginal zone B cell differentiation.","evidence":"B cell-specific Atxn1l conditional KO mice (Atxn1l-fl/fl;Cd19-Cre) with Etv4-deletion epistasis rescue and flow cytometry","pmids":["39632849"],"confidence":"High","gaps":["Whether other B cell subsets or T cell development are affected was not fully characterized","Whether this mechanism contributes to immunodeficiency phenotypes in humans is unknown"]},{"year":2025,"claim":"Whether the CIC–ATXN1L complex directly controls innate immune gene expression was unknown; identification of an 8-nucleotide binding motif at IFN/ISG promoters and demonstration that MAPK-triggered complex degradation during viral infection relieves this repression established a direct transcriptional switch for antiviral immunity.","evidence":"DNA-binding assays, CIC/ATXN1L CRISPR-KO in human and mouse cells, ChIP at IFN/ISG promoters, and viral infection models with MAPK activation","pmids":["40132591"],"confidence":"High","gaps":["Whether CIC–ATXN1L degradation kinetics differ by virus type is unknown","The relative contribution of ATXN1L loss versus CIC phosphorylation to complex dissolution is not separated"]},{"year":null,"claim":"The structural basis for how ATXN1L shields CIC from TRIM25-mediated ubiquitination, the determinants of isoform-selective CIC-S/ATXN1L versus CIC-L/ATXN1 pairing, and the full spectrum of tissue-specific CIC–ATXN1L target genes remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ATXN1L–CIC interface exists","Isoform-specific pairing determinants identified only in preprint","Genome-wide direct binding targets across tissues are not comprehensively mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,5,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,8,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,9,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,9]}],"complexes":["CIC-ATXN1L complex"],"partners":["CIC","ATXN1","TRIM25","HDAC3","CBF1"],"other_free_text":[]},"mechanistic_narrative":"ATXN1L functions as an essential stabilizer and cofactor of the transcriptional repressor CIC, forming a complex that suppresses ETS family transcription factors (ETV1/ETV4/ETV5), Notch target genes, and interferon/interferon-stimulated gene promoters. ATXN1L binding protects CIC from TRIM25-mediated polyubiquitination and proteasomal degradation; loss of ATXN1L destabilizes CIC, de-repressing downstream targets including MMPs, cell-cycle genes, and IFN/ISG loci, thereby modulating MAPK pathway sensitivity, extracellular matrix remodeling, hematopoietic stem cell quiescence, marginal zone B cell development, and antiviral innate immunity [PMID:22014525, PMID:33115448, PMID:28178529, PMID:39632849, PMID:40132591]. ATXN1L competes with its paralog ATXN1 for incorporation into the CIC complex, and elevated ATXN1L displaces polyglutamine-expanded ATXN1, suppressing spinocerebellar ataxia type 1 (SCA1) neuropathology in mice [PMID:17322884]. During viral infection, MAPK activation triggers rapid degradation of the CIC–ATXN1L complex, relieving repression of an 8-nucleotide motif at IFN/ISG promoters and enabling innate immune gene induction [PMID:40132591]."},"prefetch_data":{"uniprot":{"accession":"P0C7T5","full_name":"Ataxin-1-like","aliases":["Brother of ataxin-1","Brother of ATXN1"],"length_aa":689,"mass_kda":73.3,"function":"Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression (PubMed:21475249). Can suppress ATXN1 cytotoxicity in spinocerebellar ataxia type 1 (SCA1). In concert with CIC and ATXN1, involved in brain development (By similarity)","subcellular_location":"Nucleus; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/P0C7T5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN1L","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATXN1L","total_profiled":1310},"omim":[{"mim_id":"614301","title":"ATAXIN 1-LIKE; ATXN1L","url":"https://www.omim.org/entry/614301"},{"mim_id":"612082","title":"CAPICUA TRANSCRIPTIONAL REPRESSOR; CIC","url":"https://www.omim.org/entry/612082"},{"mim_id":"601556","title":"ATAXIN 1; ATXN1","url":"https://www.omim.org/entry/601556"},{"mim_id":"147183","title":"RECOMBINATION SIGNAL-BINDING PROTEIN FOR IMMUNOGLOBULIN KAPPA J REGION; RBPJ","url":"https://www.omim.org/entry/147183"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN1L"},"hgnc":{"alias_symbol":["BOAT1"],"prev_symbol":[]},"alphafold":{"accession":"P0C7T5","domains":[{"cath_id":"-","chopping":"468-583","consensus_level":"medium","plddt":94.054,"start":468,"end":583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C7T5","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0C7T5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0C7T5-F1-predicted_aligned_error_v6.png","plddt_mean":50.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN1L","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN1L"},"sequence":{"accession":"P0C7T5","fasta_url":"https://rest.uniprot.org/uniprotkb/P0C7T5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0C7T5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C7T5"}},"corpus_meta":[{"pmid":"28178529","id":"PMC_28178529","title":"ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28178529","citation_count":96,"is_preprint":false},{"pmid":"22014525","id":"PMC_22014525","title":"ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014525","citation_count":89,"is_preprint":false},{"pmid":"17322884","id":"PMC_17322884","title":"Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17322884","citation_count":66,"is_preprint":false},{"pmid":"21475249","id":"PMC_21475249","title":"Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21475249","citation_count":65,"is_preprint":false},{"pmid":"33782651","id":"PMC_33782651","title":"Perspectives on plant flavonoid quercetin-based drugs for novel SARS-CoV-2.","date":"2021","source":"Beni-Suef University journal of basic and applied sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33782651","citation_count":38,"is_preprint":false},{"pmid":"30093628","id":"PMC_30093628","title":"Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30093628","citation_count":30,"is_preprint":false},{"pmid":"32073140","id":"PMC_32073140","title":"Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor.","date":"2020","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32073140","citation_count":23,"is_preprint":false},{"pmid":"26639094","id":"PMC_26639094","title":"The Relevance of JAK2 in the Regulation of Cellular Transport.","date":"2016","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26639094","citation_count":16,"is_preprint":false},{"pmid":"19085187","id":"PMC_19085187","title":"Characterization of the zebrafish atxn1/axh gene family.","date":"2008","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19085187","citation_count":16,"is_preprint":false},{"pmid":"34498878","id":"PMC_34498878","title":"New Two-Dimensional Wide Band Gap Hydrocarbon Insulator by Hydrogenation of a Biphenylene Sheet.","date":"2021","source":"The journal of physical chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/34498878","citation_count":16,"is_preprint":false},{"pmid":"35084609","id":"PMC_35084609","title":"MicroRNA-136-5p protects cardiomyocytes from coronary microembolization through the inhibition of pyroptosis.","date":"2022","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/35084609","citation_count":14,"is_preprint":false},{"pmid":"35573049","id":"PMC_35573049","title":"Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice.","date":"2022","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/35573049","citation_count":13,"is_preprint":false},{"pmid":"33115448","id":"PMC_33115448","title":"TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L.","date":"2020","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/33115448","citation_count":12,"is_preprint":false},{"pmid":"35414011","id":"PMC_35414011","title":"Possible implication of miR-142-3p in coronary microembolization induced myocardial injury via ATXN1L/HDAC3/NOL3 axis.","date":"2022","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35414011","citation_count":12,"is_preprint":false},{"pmid":"32014859","id":"PMC_32014859","title":"Undifferentiated small round cell sarcoma in a young male: a case report.","date":"2020","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/32014859","citation_count":12,"is_preprint":false},{"pmid":"37845370","id":"PMC_37845370","title":"Functional implications of paralog genes in polyglutamine spinocerebellar ataxias.","date":"2023","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37845370","citation_count":12,"is_preprint":false},{"pmid":"32346919","id":"PMC_32346919","title":"Recent Advances in Pathology: the 2020 Annual Review Issue of The Journal of Pathology.","date":"2020","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32346919","citation_count":11,"is_preprint":false},{"pmid":"34768779","id":"PMC_34768779","title":"Structural Analysis and Spatiotemporal Expression of Atxn1 Genes in Zebrafish Embryos and Larvae.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34768779","citation_count":6,"is_preprint":false},{"pmid":"23555280","id":"PMC_23555280","title":"Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23555280","citation_count":6,"is_preprint":false},{"pmid":"38970674","id":"PMC_38970674","title":"MUC5AC immunoreactivity in scattered tumor cells is useful for diagnosing CIC-rearranged sarcoma.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38970674","citation_count":5,"is_preprint":false},{"pmid":"41142409","id":"PMC_41142409","title":"Mechanisms involved in aminoacidurias: impacts of genetic and environmental factors.","date":"2025","source":"Current research in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41142409","citation_count":4,"is_preprint":false},{"pmid":"39632849","id":"PMC_39632849","title":"The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39632849","citation_count":3,"is_preprint":false},{"pmid":"40132591","id":"PMC_40132591","title":"Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses.","date":"2025","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/40132591","citation_count":2,"is_preprint":false},{"pmid":"39002033","id":"PMC_39002033","title":"Evaluating the expression pattern of ATXN1 and CDC42EP1 genes and related long noncoding RNAs in oral squamous cell carcinoma.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39002033","citation_count":2,"is_preprint":false},{"pmid":"41804677","id":"PMC_41804677","title":"HMGA2 expression in CIC-rearranged sarcoma and other small round/epithelioid cell tumours.","date":"2026","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/41804677","citation_count":0,"is_preprint":false},{"pmid":"41279815","id":"PMC_41279815","title":"Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279815","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13652,"output_tokens":2876,"usd":0.042048},"stage2":{"model":"claude-opus-4-6","input_tokens":6221,"output_tokens":2410,"usd":0.137033},"total_usd":0.179081,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ATXN1L (BOAT) competes with polyglutamine-expanded ATXN1 for incorporation into the native CIC-containing complex; elevated ATXN1L levels displace mutant ATXN1 from this complex, suppressing SCA1 neuropathology in knock-in mice.\",\n      \"method\": \"Targeted duplication of mouse Atxn1l locus; genetic epistasis in SCA1 knock-in mouse model; co-immunoprecipitation demonstrating displacement of mutant ATXN1 from CIC complex\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis in vivo with multiple readouts, replicated across labs subsequently\",\n      \"pmids\": [\"17322884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN1L forms a complex with the transcriptional repressor CIC and stabilizes CIC protein; loss of ATXN1L destabilizes CIC, derepresses Etv4, and thereby activates Mmp gene expression (including MMP9), causing defects in extracellular matrix remodeling and lung alveolarization.\",\n      \"method\": \"Atxn1L knockout mice; Atxn1-/-;Atxn1L-/- double knockout mice; gene expression analysis; genetic epistasis with Cic-deficient mice\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined molecular and developmental phenotype, genetic epistasis, replicated in double-KO\",\n      \"pmids\": [\"22014525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN1L (BOAT1) and ATXN1 are components of the Notch signalling pathway; both proteins bind to the promoter region of Hey1 and inhibit Notch transcriptional output through direct interactions with CBF1.\",\n      \"method\": \"Drosophila BOAT1 functional analysis; ChIP showing binding to Hey1 promoter; co-immunoprecipitation with CBF1 in mammalian cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with functional validation in two systems, single lab\",\n      \"pmids\": [\"21475249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATXN1L deletion reduces CIC protein levels, leading to de-repression of ETS transcription factors ETV1, ETV4, and ETV5 and promoting resistance to MEK/RAF inhibitors; the ATXN1L-CIC-ETS axis modulates sensitivity to MAPK pathway inhibition.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 loss-of-function screens; ATXN1L deletion validated in cancer cell lines; ectopic ETV1/4/5 expression phenocopying ATXN1L loss\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale CRISPR screen with orthogonal genetic validation across multiple cell lines\",\n      \"pmids\": [\"28178529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATXN1L regulates hematopoietic stem cell (HSC) quiescence; Atxn1L-null mice have greater numbers of HSCs with higher proliferation rates and gene expression changes consistent with reduced quiescence.\",\n      \"method\": \"Atxn1L knockout mice; in vitro and in vivo HSC functional assays; molecular gene expression analyses\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and molecular characterization, single lab\",\n      \"pmids\": [\"23555280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATXN1L and CIC have a reciprocal functional relationship: loss of either affects target gene regulation; the CIC-ATXN1-ATXN1L axis regulates cell cycle and mitotic division gene programs.\",\n      \"method\": \"ATXN1LKO and CICKO human cell lines; transcriptomic analysis; functional in vitro studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal KO cell lines with transcriptomic readout, single lab\",\n      \"pmids\": [\"30093628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of ATXN1L leads to polyubiquitination and proteasomal degradation of CIC protein, mediated by the E3 ubiquitin ligase TRIM25, independently of ERK activity.\",\n      \"method\": \"ATXN1LKO human cell lines; proteasome inhibitor assays; TRIM25 knockdown/overexpression; ubiquitination assays; validation in glioma-derived cell lines\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, ubiquitination assay, TRIM25 KD, inhibitor treatment) in multiple cell systems, single lab\",\n      \"pmids\": [\"33115448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-136-5p targets ATXN1L; ATXN1L binds CIC to suppress PYDC1 expression, thereby promoting pyroptosis in cardiomyocytes; miR-136-5p suppresses pyroptosis by inhibiting ATXN1L/CIC binding.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-136-5p targeting ATXN1L); co-immunoprecipitation (ATXN1L-CIC interaction); cell transfection with ATXN1L overexpression/knockdown; LPS-induced pyroptosis model\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and reporter assay in a single lab, novel cardiomyocyte context without independent replication\",\n      \"pmids\": [\"35084609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATXN1L promotes deacetylation of histone H3 through recruitment of HDAC3 to the NOL3 promoter, thereby inhibiting NOL3 expression and promoting cardiomyocyte apoptosis and pyroptosis.\",\n      \"method\": \"ChIP (ATXN1L and HDAC3 binding to NOL3 promoter); ATXN1L knockout adenovirus in rats; HDAC3 inhibition; immunofluorescence for HDAC3 localization; immunoprecipitation for HDAC3-H3 binding\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and Co-IP in a single lab; novel mechanism not independently replicated\",\n      \"pmids\": [\"35414011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The CIC-ATXN1L complex represses Notch signaling in marginal zone B cells by suppressing ETV4; ATXN1L deficiency specifically de-represses ETV4, which inhibits Notch1 and Notch2 transcription and thereby impairs marginal zone B cell development.\",\n      \"method\": \"B cell-specific Atxn1l conditional knockout mice (Atxn1lf/f;Cd19-Cre); Etv4-deletion epistasis; flow cytometry; Notch signaling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genetic epistasis (Etv4-deletion rescue), defined cellular phenotype, multiple in vivo readouts\",\n      \"pmids\": [\"39632849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CIC-ATXN1L transcriptional repressor complex binds an 8-nucleotide motif near interferon (IFN) and IFN-stimulated gene (ISG) promoters and prevents their basal expression; MAPK pathway activation during viral infection triggers rapid degradation of the CIC-ATXN1L complex, relieving repression and allowing IFN/ISG induction.\",\n      \"method\": \"DNA-binding assays identifying 8-nt motif; CRISPR KO of CIC and ATXN1L in human and mouse cells; viral infection models; MAPK activation studies; ChIP for complex binding at IFN/ISG promoters\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KO, motif binding, viral infection), validated in both human and mouse systems\",\n      \"pmids\": [\"40132591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CIC short isoform (CIC-S) preferentially interacts with ATXN1L, while CIC long isoform (CIC-L) preferentially interacts with ATXN1; loss of CIC-S causes perinatal lethality phenocopying ATXN1L knockout, whereas loss of CIC-L causes cognitive deficits phenocopying ATXN1 knockout, demonstrating isoform-specific paralog interactions.\",\n      \"method\": \"Mouse knockin models expressing only CIC-L or CIC-S; co-immunoprecipitation showing isoform-selective interactions with ATXN1 vs ATXN1L; behavioral and developmental phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with isoform-specific knockin mice and phenotypic validation; preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279815\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATXN1L functions primarily as a binding partner and stabilizer of the transcriptional repressor CIC, forming a complex that suppresses ETS transcription factors (ETV1/4/5), Notch target genes, and interferon/ISG promoters; when ATXN1L is lost, the E3 ubiquitin ligase TRIM25 polyubiquitinates CIC for proteasomal degradation, de-repressing downstream targets and modulating MAPK pathway sensitivity, ECM remodeling, B cell development, HSC quiescence, and antiviral innate immunity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATXN1L functions as an essential stabilizer and cofactor of the transcriptional repressor CIC, forming a complex that suppresses ETS family transcription factors (ETV1/ETV4/ETV5), Notch target genes, and interferon/interferon-stimulated gene promoters. ATXN1L binding protects CIC from TRIM25-mediated polyubiquitination and proteasomal degradation; loss of ATXN1L destabilizes CIC, de-repressing downstream targets including MMPs, cell-cycle genes, and IFN/ISG loci, thereby modulating MAPK pathway sensitivity, extracellular matrix remodeling, hematopoietic stem cell quiescence, marginal zone B cell development, and antiviral innate immunity [PMID:22014525, PMID:33115448, PMID:28178529, PMID:39632849, PMID:40132591]. ATXN1L competes with its paralog ATXN1 for incorporation into the CIC complex, and elevated ATXN1L displaces polyglutamine-expanded ATXN1, suppressing spinocerebellar ataxia type 1 (SCA1) neuropathology in mice [PMID:17322884]. During viral infection, MAPK activation triggers rapid degradation of the CIC–ATXN1L complex, relieving repression of an 8-nucleotide motif at IFN/ISG promoters and enabling innate immune gene induction [PMID:40132591].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether ATXN1L participates in the same complex as ATXN1 was unknown; demonstrating that ATXN1L competes with mutant ATXN1 for the native CIC-containing complex established it as a functional paralog and potential modifier of SCA1 disease.\",\n      \"evidence\": \"Targeted duplication of mouse Atxn1l locus plus co-immunoprecipitation in SCA1 knock-in mice showing displacement of mutant ATXN1\",\n      \"pmids\": [\"17322884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for competitive binding not determined\", \"Whether ATXN1L and ATXN1 have non-overlapping functions beyond CIC complex occupancy was unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The molecular consequence of ATXN1L loss was unknown; knockout studies revealed that ATXN1L stabilizes CIC protein and that its absence de-represses ETV4/MMP targets causing lung alveolarization defects, establishing the ATXN1L–CIC–ETS axis as a physiological regulatory module.\",\n      \"evidence\": \"Atxn1L single and Atxn1/Atxn1L double knockout mice with gene expression and developmental phenotyping; ChIP and co-IP showing ATXN1L binding at Notch target (Hey1) promoters with CBF1\",\n      \"pmids\": [\"22014525\", \"21475249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ATXN1L stabilizes CIC protein was not identified\", \"Whether Notch regulation via CBF1 is CIC-dependent or represents an independent ATXN1L function was unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether ATXN1L regulates stem cell biology was untested; Atxn1L-null mice showed expanded, hyperproliferative HSCs, linking the CIC-stabilizing function to maintenance of hematopoietic stem cell quiescence.\",\n      \"evidence\": \"Atxn1L knockout mice with in vivo and in vitro HSC assays and molecular profiling\",\n      \"pmids\": [\"23555280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HSC phenotype is CIC-dependent was not formally tested with epistasis\", \"Downstream gene programs driving quiescence loss were not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether the ATXN1L–CIC axis has therapeutic relevance was unknown; genome-scale CRISPR screens identified ATXN1L loss as a driver of resistance to MEK/RAF inhibitors through de-repression of ETV1/4/5, connecting this complex to MAPK pathway drug sensitivity in cancer.\",\n      \"evidence\": \"Genome-scale CRISPR-Cas9 screens in cancer cell lines; ectopic ETV expression phenocopying ATXN1L loss\",\n      \"pmids\": [\"28178529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether restoring ATXN1L or CIC can re-sensitize resistant tumors was not tested\", \"Relative contribution of individual ETV factors to resistance was not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The biochemical mechanism by which CIC is destabilized upon ATXN1L loss was unknown; identification of TRIM25 as the E3 ligase that polyubiquitinates CIC for proteasomal degradation — independently of ERK activity — provided the missing proteolytic link.\",\n      \"evidence\": \"ATXN1L-KO human cell lines with proteasome inhibitor treatment, ubiquitination assays, and TRIM25 knockdown/overexpression across multiple cell systems\",\n      \"pmids\": [\"33115448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATXN1L physically shields CIC from TRIM25 access is unknown\", \"Whether additional E3 ligases contribute in other tissues was not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether the ATXN1L–CIC–ETV4 axis operates in immune cell development was untested; conditional B cell-specific knockout demonstrated that ATXN1L deficiency de-represses ETV4, which in turn suppresses Notch1/2 transcription and impairs marginal zone B cell differentiation.\",\n      \"evidence\": \"B cell-specific Atxn1l conditional KO mice (Atxn1l-fl/fl;Cd19-Cre) with Etv4-deletion epistasis rescue and flow cytometry\",\n      \"pmids\": [\"39632849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other B cell subsets or T cell development are affected was not fully characterized\", \"Whether this mechanism contributes to immunodeficiency phenotypes in humans is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether the CIC–ATXN1L complex directly controls innate immune gene expression was unknown; identification of an 8-nucleotide binding motif at IFN/ISG promoters and demonstration that MAPK-triggered complex degradation during viral infection relieves this repression established a direct transcriptional switch for antiviral immunity.\",\n      \"evidence\": \"DNA-binding assays, CIC/ATXN1L CRISPR-KO in human and mouse cells, ChIP at IFN/ISG promoters, and viral infection models with MAPK activation\",\n      \"pmids\": [\"40132591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CIC–ATXN1L degradation kinetics differ by virus type is unknown\", \"The relative contribution of ATXN1L loss versus CIC phosphorylation to complex dissolution is not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how ATXN1L shields CIC from TRIM25-mediated ubiquitination, the determinants of isoform-selective CIC-S/ATXN1L versus CIC-L/ATXN1 pairing, and the full spectrum of tissue-specific CIC–ATXN1L target genes remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the ATXN1L–CIC interface exists\", \"Isoform-specific pairing determinants identified only in preprint\", \"Genome-wide direct binding targets across tissues are not comprehensively mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 5, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 9, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [\n      \"CIC-ATXN1L complex\"\n    ],\n    \"partners\": [\n      \"CIC\",\n      \"ATXN1\",\n      \"TRIM25\",\n      \"HDAC3\",\n      \"CBF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}