ASXL3 is a nuclear chromatin regulator and noncatalytic partner of the BAP1 deubiquitinase complex PR-DUB. Its DEUBAD region activates BAP1, while a separate BRD4-binding region bridges BRD4 to the BAP1 complex and supports enhancer recruitment in human small cell lung cancer cells. PHD-associated MBD proteins contribute to complex organization. ASXL3 can promote transcription in enhancer-associated contexts and repress nuclear-receptor programs in other settings. Disruption of ASXL3 causes Bainbridge-Ropers syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003677 DNA binding | IEA GO_REF:0000002 | UNDECIDED | Summary: Direct DNA binding by the mapped PHD domain is unresolved. Reason: The source is specifically InterPro:IPR026905, not the separate HARE-HTH domain. ASXL3 PHD association with MBD5/6 supports a protein interface, while chromatin occupancy can result from partner recruitment. Neither observation demonstrates direct DNA recognition or its absence. Preserve the electronic assertion without inventing a negative assay. Propagation Review Root cause: UNRESOLVED Sources checked: InterPro:IPR026905 UNRESOLVED This source is the ASX-like PHD mapping. MBD5/6 interaction and chromatin occupancy do not adjudicate direct DNA recognition by this domain; the mapping remains unresolved. |
| GO:0003682 chromatin binding | IBA GO_REF:0000033 | ACCEPT | Summary: ASXL3 associates with chromatin in human cells. Reason: The PAINT inference is consistent with target-specific ASXL3 chromatin occupancy in human SCLC. This is chromatin association, not proof of direct sequence-specific DNA binding or assignment of a reader activity to the PHD alone. The ancestral tree and donor experiments were not independently reconstructed. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The nucleus is a principal site of ASXL3 chromatin regulation. Reason: The curated UniProt nuclear location is corroborated by nuclear-complex and chromatin assays. The data do not resolve localization of the two listed protein products separately. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: ASXL3 regulates transcription through chromatin-associated partners. Reason: Target studies support both activation in SCLC and repression in a receptor-specific hepatic model. The broad existing transcription-regulation term accommodates these contexts. Its HARE-HTH source does not establish sequence-specific DNA recognition by that domain. |
| GO:0009887 animal organ morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The existing developmental inference is retained as a broader organismal role. Reason: Retain the curated PAINT assertion in the context of ASXL3-dependent chromatin regulation and human developmental disease. Its ancestral placement and every donor experiment remain unread; disease phenotypes alone are not being used to propose a new organ-specific process or a separate molecular function. Supporting Evidence: |
| GO:0035517 PR-DUB complex | IBA GO_REF:0000033 | ACCEPT | Summary: ASXL3 is a noncatalytic PR-DUB regulatory partner. Reason: ASXL3-BAP1 association in cellular studies and activation by purified human ASXL3 DEUBAD corroborate the existing complex-membership IBA. BAP1 performs deubiquitination; ASXL3 contributes activation and partner organization. The donor list is retained as evidence for an ancestral assertion, not treated as a pairwise transfer. |
| GO:0042975 peroxisome proliferator activated receptor binding | IBA GO_REF:0000033 | UNDECIDED | Summary: The specific PPAR-binding ancestral inference remains unresolved. Reason: The mapped PAINT node is PTN000339788. Target receptor experiments address LXRalpha and TRbeta, which are not PPARs. They neither establish nor refute PPAR recognition. The available family export lacks the ancestral tree, IBD placement and alignment needed to assess this node; donor count is not evidence against it. Preserve the original source and refrain from substituting a different receptor assertion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000339788 UNRESOLVED The source is the PAINT ancestral node. Its IBD placement and alignment were not recovered; target LXRalpha/TRbeta assays neither establish nor refute PPAR recognition. Supporting Evidence: |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ASXL3 promotes RNA polymerase II transcription in relevant chromatin contexts. Reason: The existing IBA is corroborated by ASXL3-dependent chromatin recruitment and gene expression in human SCLC. Repression in another receptor/cell context is compatible with this activating role. No reconstruction of the PAINT ancestral placement or universal direction of transcriptional effect is claimed. |
| GO:0051055 negative regulation of lipid biosynthetic process | IDA PMID:25450400 Repression of LXRΞ± by a novel member of additional sex comb-... | KEEP AS NON CORE | Summary: ASXL3 represses a lipid-associated transcriptional program in the studied hepatic context. Reason: The original abstract describes LXRalpha/TRbeta-associated repression and reciprocal lipid-accumulation effects of ASXL3 overexpression and depletion in Hep3B cells. Retain the curator-assigned experimental process as contextual. Complete Methods and biosynthetic-flux assays remain unread; this does not establish intrinsic lipid catalysis or a universal metabolic function. Supporting Evidence: |
| GO:0035800 deubiquitinase activator activity | IDA PMID:26739236 BAP1/ASXL1 recruitment and activation for H2A deubiquitinati... | NEW | Summary: The human ASXL3 DEUBAD region directly activates BAP1. Reason: Purified human Q9C0F0 DEUBAD residues 244-360 stimulate BAP1-mediated removal of nucleosomal H2A-K119 ubiquitin in PMID:26739236 Figure 1e. The construct is bacterially expressed and BAP1 produced separately in Sf9 cells. This establishes activator work by ASXL3 rather than intrinsic hydrolase activity. The original nine rows lack this specific molecular function, and the fragment experiment does not establish activity of every full-length alternative product. Supporting Evidence: PMID:26739236 These results establish that the DEUBAD domains in all human ASXL paralogs can stimulate BAP1 activity. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:32669118 ASXL3 bridges BRD4 to BAP1 complex and governs enhancer acti... | NEW | Summary: ASXL3 bridges BRD4 and the BAP1 complex through separable interaction regions. Reason: PMID:32669118 Figures 2 and 3 support an adaptor activity distinct from DEUBAD-mediated BAP1 activation. Endogenous human NCI-H1963 co-immunoprecipitation places ASXL3 with BAP1 and BRD4, while human ASXL3 expression in HEK293T cells increases BAP1-BRD4 association. Deleting the 20-residue BRD4-binding motif abolishes BRD4 association while retaining BAP1 association. Purified recombinant ASXL3 BBM and BRD4 ET fragments bind directly. ASXL3 depletion reduces BRD4 enhancer occupancy without lowering total BRD4 protein. The combination supports bridging rather than generic binding alone; it does not establish direct DNA recognition, an activity of every alternative product, or universal exclusion of other ASXL paralogs from BRD4 binding. Supporting Evidence: PMID:32669118 depletion of the 20 amino acids (ΞBBM) does not affect ASXL3/BAP1 interaction, but only completely abolished ASXL3/BRD4 interaction |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does the ASXL3 PHD domain directly bind DNA, separately from MBD5/6 association and indirect chromatin recruitment?
Q: Which PAINT ancestral evidence supports the PTN000339788 PPAR-binding inference for ASXL3, separately from the demonstrated LXRalpha and TRbeta interactions?
Q: Does the Q9C0F0-2 product, with replacement of residues 294-317 and loss of residues 318-2248 in the UniProt record, form a stable functional protein, and which BAP1-activation or recruitment functions does it retain? The assayed human DEUBAD fragment spans residues 244-360, so its result cannot be transferred automatically to this shortened product.
Experiment: Compare purified full-length ASXL3 products and matched DEUBAD, BBM and PHD variants for BAP1 activation, BRD4 association and MBD6-dependent assembly.
Hypothesis: Distinct interfaces separate deubiquitinase activation from recruitment and complex stabilization.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)