ASXL1 is a nuclear chromatin regulator containing HARE-HTH, DEUBAD and PHD regions. As a noncatalytic component of the BAP1-containing PR-DUB complex, it activates BAP1 and helps position nucleosomal DNA and monoubiquitinated histone H2A for deubiquitination. ASXL1 also participates in transcriptional coactivation and context-dependent nuclear-receptor regulation. These chromatin functions influence developmental gene expression and cellular identity. Pathogenic variants cause Bohring-Opitz syndrome, and somatic alterations occur in myeloid neoplasia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: DNA engagement contributes to nucleosome positioning by PR-DUB. Reason: Human ASXL1 DEUBAD contacts nucleosomal DNA in the PR-DUB structure (PMID:37556531), supporting broad DNA binding. A separate HARE-HTH oligonucleotide pull-down study (PMID:30982744) is distinct evidence. Neither experiment establishes DNA recognition by the PHD region that generated the original InterPro mapping; that mapping and physiological methylated-DNA specificity remain unresolved. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR026905 UNRESOLVED IPR026905 is the PHD-family mapping. The exact domain-to-DNA-binding inference remains unresolved; DEUBAD structural contact and HARE-HTH oligonucleotide binding do not validate PHD DNA recognition. |
| GO:0003682 chromatin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Chromatin binding is integral to ASXL1 function. Reason: ASXL1 engages chromatin as the noncatalytic activator and substrate-positioning component of human PR-DUB. Direct human evidence corroborates the biological assertion; no defect in the PAINT node placement has been established. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000339786 UNRESOLVED PTN000339786 is the proximate ancestral assertion. The source list includes fly Asx and mouse Asxl2 (MGI:1922552); their exact experimental contribution to this node and the tree placement were not reconstructed. Human ASXL1 structural evidence independently corroborates chromatin engagement. |
| GO:0003713 transcription coactivator activity | ISS GO_REF:0000024 | ACCEPT | Summary: ASXL1 contributes transcriptional coactivator activity. Reason: The receptor study supports ligand-dependent coactivation with SRC-1, and human PR-DUB studies establish a broader transcriptional coactivator role. The original mouse P59598 transfer is retained; human receptor-binding fragments are distinguished from full-length mouse cellular coactivation assays. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 is the ortholog source. Mouse ASXL1 receptor/reporter coactivation and separately tested human receptor-binding fragments support the transfer; human chromatin studies corroborate transcriptional function. |
| GO:0005515 protein binding | IPI PMID:16606617 Additional sex comb-like 1 (ASXL1), in cooperation with SRC-... | MODIFY | Summary: Refine the human ESR1 interaction to nuclear receptor binding. Reason: Original Figure 5A in PMID:16606617 tests human ASXL1 residues 1096–1541 with human ESR1 in a GST pull-down using in-vitro-translated receptor. The primary-paper URL and caption/Methods text-reading scope are recorded in the gene notes; the repository cache remains abstract-only. Nuclear receptor binding describes this measured interaction, preserving P03372 as the source partner. Proposed replacements: nuclear receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16606617 Additional sex comb-like 1 (ASXL1), in cooperation with SRC-... | MODIFY | Summary: Refine the mouse RXRalpha interaction to nuclear receptor binding. Reason: Original Figure 5A in PMID:16606617 tests human ASXL1 residues 1096–1541 with mouse RXRalpha P28700 in the same GST pull-down series. Nuclear receptor binding describes this xenogeneic experiment. The gene notes identify the primary caption and targeted Methods reading; no purified binary affinity or human RXRalpha assay is inferred. Proposed replacements: nuclear receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16606617 Additional sex comb-like 1 (ASXL1), in cooperation with SRC-... | MODIFY | Summary: Refine the chicken thyroid-receptor interaction to nuclear receptor binding. Reason: Original Figure 5A in PMID:16606617 tests human ASXL1 residues 1096–1541 with chicken THRB P68306. Nuclear receptor binding describes the measured interaction while preserving its partner and species. The primary-paper caption/Methods text and official partner identities are documented in the gene notes; the cache remains abstract-only. Proposed replacements: nuclear receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:18624398 Protein interaction data set highlighted with human Ras-MAPK... | UNDECIDED | Summary: The source-specific AKT1 interaction remains unresolved. Reason: The exact ASXL1–AKT1 assay underlying PMID18624398 has not been inspected. UniProt reports AKT1 with NbExp=3, which is positive curated evidence, not an absence of support. Leave this source-specific claim unresolved rather than reject it or infer an activator MF from association. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | UNDECIDED | Summary: The original proteomic BAP1 interaction record remains unresolved. Reason: BAP1–ASXL1 biology is independently established, but the exact CompPASS/Table S3 edge and construct supporting PMID:19615732 were not read. The complete cached abstract and targeted general Methods describe the interaction-proteomics approach without resolving this specific record. Retain the assertion as undecided pending target evidence; general biological plausibility does not identify the original pair-level experiment. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20436459 Histone H2A deubiquitinase activity of the Polycomb repressi... | MODIFY | Summary: Refine BAP1 association to deubiquitinase activator activity. Reason: PMID:20436459 reconstitutes human BAP1 with ASXL1 residues 2–365 and measures ASXL1-dependent nucleosomal H2A deubiquitination. This own-source activity experiment supports deubiquitinase activation, with later human structural evidence explaining substrate positioning. BAP1 supplies the hydrolytic active site. This is stronger functional evidence than co-association alone and does not convert other BAP1 interaction records into activity assays. Proposed replacements: deubiquitinase activator activity |
| GO:0005515 protein binding | IPI PMID:22897849 ASXL1 mutations promote myeloid transformation through loss ... | KEEP AS NON CORE | Summary: Retain the EED co-association as contextual evidence. Reason: Endogenous EED immunoprecipitation in human leukemia cells supports ASXL1 co-association (PMID:22897849, Figure 6C). Retain this contextual association; the assay does not establish a separate ASXL1 enzymatic function. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22897849 ASXL1 mutations promote myeloid transformation through loss ... | KEEP AS NON CORE | Summary: Retain the EZH2 co-association as contextual evidence. Reason: Human ASXL1/EZH2 transfection and endogenous leukemia-cell co-immunoprecipitation, including benzonase controls, support the relationship (PMID:22897849). This contextual PRC2 association is distinct from the BAP1 activation mechanism. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22897849 ASXL1 mutations promote myeloid transformation through loss ... | KEEP AS NON CORE | Summary: Retain the reported BAP1 co-immunoprecipitation as contextual evidence. Reason: PMID:22897849 Figure 2A reports ASXL1–BAP1 co-immunoprecipitation, while the same study distinguishes BAP1 and ASXL1 depletion effects on HOXA expression. Retain this measured association as contextual evidence. The independent activity reconstitution in PMID:20436459 supports the narrower activator replacement on that separate source row; it does not change what this co-IP experiment demonstrates. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | UNDECIDED | Summary: The Polycomb-complexome BAP1 record remains unresolved. Reason: BAP1 binding is corroborated independently and UniProt records NbExp=9, but the exact PMID27705803 ASXL1 edge/assay has not been inspected. Do not infer source-specific activation from the broad interactome abstract or remove a plausible experimental assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The GOLGA6L9 interaction record remains unresolved. Reason: The PMID:32296183 ASXL1–GOLGA6L9 pair, construct and validation record remain unread, although article text is cached. UniProt NbExp=3 is positive curated evidence. The uncertainty concerns the exact target experiment rather than absence of a paper or evidence that the pair is false. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | UNDECIDED | Summary: The source-specific BAP1 interactome record remains unresolved. Reason: The PMID:33961781 cache contains partial article text, including Introduction and Discussion, but not the target-specific Results, Methods or pair matrix needed to resolve this ASXL1–BAP1 record. Its full-text availability flag is preserved. UniProt NbExp=9 and independent BAP1 mechanisms corroborate plausibility without resolving the cited edge. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | UNDECIDED | Summary: The mutation-screen AKT1 interaction record remains unresolved. Reason: The PMID:35512704 cache contains partial article text, including Introduction and Discussion, but the ASXL1–AKT1 target edge, construct and relevant Results/Methods or pair table remain unread. Its full-text availability flag is preserved. UniProt NbExp=3 is positive corroboration; this source-specific uncertainty is separate from the policy question about generic binding. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization supports the central chromatin-regulatory role. Reason: The nuclear localization agrees with the fetched UniProt record, human chromatin experiments and receptor-regulatory activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0191 UNRESOLVED SL-0191 is the UniProt nuclear-location vocabulary source, not a phylogenetic node. Nuclear chromatin and receptor experiments corroborate localization; the original vocabulary mapping was not independently reconstructed. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5689630 | ACCEPT | Summary: Nucleoplasmic localization agrees with independent ASXL1 evidence. Reason: Independent human ASXL1 chromatin studies support nucleoplasmic function. Reactome R-HSA-5689630 foregrounds the BAP1/YY1/HCFC1 assembly; its nested participant graph was not traversed, so that summary alone is not treated as an ASXL1-specific localization assay. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5690790 | ACCEPT | Summary: Nucleoplasmic PR-DUB localization is supported. Reason: The Reactome event explicitly places the BAP1–ASXL PR-DUB complex in nucleosomal H2A deubiquitination, agreeing with the central nuclear chromatin function. Supporting Evidence: |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Transcription regulation is a central ASXL1 role. Reason: ASXL1 regulates transcription through chromatin-associated PR-DUB and nuclear-receptor coactivation. The broad InterPro-derived biological conclusion is sound; the exact domain-to-term mapping remains separately unresolved. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR007759 UNRESOLVED IPR007759 is the HARE-HTH-associated mapping. Transcriptional regulation is independently supported, but the specific domain-to-process inference was not reconstructed and is not a PHD or PAINT assertion. |
| GO:0009887 animal organ morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Organ morphogenesis is a developmental context of ASXL1 function. Reason: Retain the existing PAINT assertion as a non-core developmental role. Published mouse Asxl1 disruption causes structural skeletal and other developmental abnormalities, while human ASXL1 variants cause a congenital-malformation syndrome. These source-specific observations are documented with access limits in the gene notes. The PAINT node placement was not independently reconstructed, and no new developmental annotation is proposed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000339786 UNRESOLVED PTN000339786 is the proximate ancestral assertion. MGI:1922552 is mouse Asxl2 and MGI:2684063 is mouse Asxl1. The source list and independent developmental papers do not reconstruct the exact node placement; the developmental observations are documented with limits in the gene notes. Supporting Evidence: file:human/ASXL1/ASXL1-notes.md Mouse Asxl1 disruption produces structural developmental abnormalities; human ASXL1 variants cause a congenital-malformation syndrome. |
| GO:0032526 response to retinoic acid | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retinoic-acid response is a receptor-specific regulatory context. Reason: The receptor study supports retinoic-acid responsiveness in the context of coactivation. Preserve the mouse ortholog evidence without making this response a separate core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 receptor/reporter experiments support retinoic-acid-responsive coactivation. This is an ortholog transfer, not a PAINT node, and the measured cellular response remains contextual. Supporting Evidence: |
| GO:0035359 negative regulation of peroxisome proliferator activated receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PPAR repression is a context-dependent regulatory role. Reason: The PPAR study supports repression in mouse-ASXL1 expression and adipocyte experiments. Human endogenous ASXL1 also co-associates with transfected PPARgamma, corroborating binding rather than every functional assay. The retracted 2009 HP1/LSD1 claim is not used as independent support. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 expression and 3T3-L1 assays support the PPAR repression context; endogenous human ASXL1 co-IP separately supports receptor association, not every mouse functional endpoint. Supporting Evidence: |
| GO:0035517 PR-DUB complex | IBA GO_REF:0000033 | ACCEPT | Summary: PR-DUB membership is conserved and directly corroborated in human. Reason: Human BAP1–ASXL1 reconstitution directly corroborates PR-DUB membership. The target Q8IXJ9 in WITH/FROM is legitimate descendant evidence, not circular support; the ancestral placement itself was not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000339786 UNRESOLVED PTN000339786 is the proximate ancestral assertion. Human Q8IXJ9 is legitimate experimental descendant evidence, not circularity; human PR-DUB reconstitution corroborates the activity. The ancestral placement itself was not reconstructed. |
| GO:0035517 PR-DUB complex | IDA PMID:20436459 Histone H2A deubiquitinase activity of the Polycomb repressi... | ACCEPT | Summary: Human ASXL1 is a reconstituted PR-DUB component. Reason: PMID:20436459 directly reconstitutes a stable human BAP1–ASXL1(2–365) complex. The paper contains human biochemical experiments despite its extensive Drosophila genetics. Supporting Evidence: |
| GO:0035517 PR-DUB complex | IPI PMID:20436459 Histone H2A deubiquitinase activity of the Polycomb repressi... | ACCEPT | Summary: Human BAP1 and ASXL1 form a stable PR-DUB complex. Reason: The same human reconstitution supports physical membership of ASXL1 in PR-DUB. Preserve this IPI assertion separately from the seeded IDA record. Supporting Evidence: |
| GO:0042974 obsolete nuclear retinoic acid receptor binding | ISS GO_REF:0000024 | MODIFY | Summary: Replace the obsolete receptor term with current nuclear receptor binding. Reason: The official GO change merged on 2026-08-24 obsoletes GO:0042974 with consider GO:0016922. Nuclear receptor binding is a supported replacement for the retained mouse-derived assertion. Keep the original obsolete ID and label as the source record; consider is not an automatic replaced_by mapping. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 receptor evidence supports nuclear receptor binding. The obsolete source term is preserved and the current replacement is reasoned from biology and the official consider relation, not an automatic ontology substitution. Proposed replacements: nuclear receptor binding Supporting Evidence: |
| GO:0042975 peroxisome proliferator activated receptor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PPAR binding is a supported receptor-specific context. Reason: The PPAR study, including endogenous human ASXL1 co-association, corroborates this receptor context. The source list contains mouse Asxl1 (MGI:2684063) and human ASXL2 (Q76L83); these distinct identities do not by themselves establish an error in the PTN000339788 ancestral assertion. Its topology and node placement were not reconstructed. The inspected ontology obsoletion does not include GO:0042975. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000339788 UNRESOLVED PTN000339788 is the proximate ancestral assertion. MGI:2684063 denotes mouse Asxl1, whereas Q76L83 denotes human ASXL2. The PPAR experiments distinguish mouse ASXL1 expression from endogenous human ASXL1 co-association. Different node identifiers alone do not establish functional divergence. Supporting Evidence: |
| GO:0042975 peroxisome proliferator activated receptor binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the ortholog-supported PPAR-binding activity as non-core. Reason: The mouse P59598 transfer agrees with the 2011 binding experiments and human endogenous ASXL1 co-association. Preserve the ortholog source; this receptor-specific activity is contextual. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 binding experiments are the ortholog basis. Human endogenous ASXL1 co-association provides corroboration, while receptor-specific binding remains a contextual activity. Supporting Evidence: |
| GO:0045599 negative regulation of fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adipocyte differentiation is a contextual downstream phenotype. Reason: Mouse ASXL1 expression and depletion experiments in 3T3-L1 cells support a negative effect on adipocyte differentiation. Retain the existing ortholog inference as a downstream context of transcriptional regulation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 expression/depletion in 3T3-L1 supports the differentiation endpoint. This remains a qualified human ortholog inference rather than a directly tested human adipocyte result. Supporting Evidence: |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of PolII transcription is core coactivator function. Reason: Positive transcription regulation is integral to the coactivator role and is corroborated by human PR-DUB studies. No evidence of target-specific loss or faulty PAINT placement has been established. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000339786 UNRESOLVED PTN000339786 is the proximate ancestral assertion. The preserved source list includes mouse Asxl1 (MGI:2684063) and human ASXL2 (Q76L83). Human ASXL1/2 PR-DUB studies corroborate transcriptional regulation, but the exact PAINT placement was not independently reconstructed. Supporting Evidence: |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: The ortholog-supported transcriptional coactivation is biologically sound. Reason: Mouse receptor coactivation and independent human chromatin evidence support the biological conclusion. Promoter histone acetylation is an output of coactivation, not ASXL1 histone-acetyltransferase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 receptor/reporter coactivation supports the transfer; human PR-DUB evidence separately corroborates transcriptional activation. Histone acetylation is an output, not intrinsic ASXL1 catalytic activity. |
| GO:0048386 positive regulation of retinoic acid receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retinoic-acid receptor signaling is a specific coactivation context. Reason: Retinoic-acid receptor signaling enhancement is a supported specific context of transcriptional coactivation. Preserve the ortholog-supported assertion as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59598 UNRESOLVED Mouse P59598 receptor-reporter assays support the retinoic-acid signaling context. Human receptor-binding fragments corroborate an interface without turning the mouse signaling endpoint into human IDA. Supporting Evidence: |
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Q: How do full-length human ASXL1 products differ in PR-DUB activation and receptor-dependent transcriptional regulation?
Q: How should experimentally supported generic protein-binding rows be represented when no narrower activity is shown, given the user action definition that REMOVE means likely incorrect biology? This policy question is separate from the six unresolved source-specific interaction records.
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