Affinage

ASXL3

Putative Polycomb group protein ASXL3 · UniProt Q9C0F0

Length
2248 aa
Mass
241.9 kDa
Annotated
2026-06-09
41 papers in source corpus 6 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASXL3 is a chromatin-associated scaffold protein that controls histone H2A mono-ubiquitination and enhancer-dependent transcription with consequences for neurodevelopment and tumor growth (PMID:26647312, PMID:32669118). It physically associates with BAP1, the catalytic subunit of the Polycomb Repressive Deubiquitination (PR-DUB) complex, and is required for PR-DUB-mediated removal of H2AK119 mono-ubiquitin: loss of ASXL3 in patient fibroblasts elevates H2AK119Ub1 and dysregulates the transcriptome (PMID:26647312). ASXL3 additionally acts as an adaptor that directly bridges BRD4 to the BAP1 complex, binding the BRD4 extra-terminal domain through a dedicated BRD4-binding motif to maintain BRD4 occupancy and H3K27Ac at active enhancers; its depletion reduces genome-wide H3K27Ac and BRD4-dependent gene expression (PMID:32669118). Pharmacologic inhibition of BAP1 catalytic activity destabilizes the ASXL3 scaffold and collapses ASCL1/MYCL/E2F neuroendocrine programs, impairing small-cell lung cancer viability and tumor growth (PMID:35194152). Independently, ASXL3 serves as a ligand-dependent transcriptional corepressor of the nuclear receptors LXRα and TRβ, recruiting HP1α and LSD1 to response elements and restraining LXRα target genes and lipid accumulation (PMID:25450400). Truncating mutations in Bainbridge-Ropers syndrome patients produce ASXL3 transcripts subject to nonsense-mediated decay, lowering ASXL3 protein and disrupting H2AK119Ub1 regulation (PMID:26647312).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2014 Medium

    Before its chromatin-complex role was defined, it was unknown how ASXL3 influenced transcription; this work established it as a ligand-dependent corepressor of nuclear receptors coupled to chromatin-modifying machinery.

    Evidence GST pull-down, co-IP, and ChIP at LXR-response elements with gain/loss-of-function and lipid assays in Hep3B cells

    PMID:25450400

    Open questions at the time
    • Does not connect this corepressor activity to the PR-DUB/BAP1 axis
    • Structural basis of HP1α/LSD1 recruitment unresolved
    • Single cell-line model
  2. 2015 High

    It was unclear which chromatin complex ASXL3 operated in; demonstrating BAP1 interaction and elevated H2AK119Ub1 upon ASXL3 loss placed it within the PR-DUB complex as a required deubiquitination cofactor.

    Evidence Reciprocal Co-IP of ASXL3 with BAP1 and quantitative H2AK119Ub1 western blot with RNA-seq in patient fibroblasts

    PMID:26647312

    Open questions at the time
    • Stoichiometry and assembly of ASXL3 within PR-DUB not defined
    • Genome-wide H2AK119Ub1 occupancy not mapped
    • Direct vs indirect deubiquitination requirement not separated
  3. 2015 Medium

    How disease-associated mutations impair ASXL3 was unknown; showing truncating mutations trigger nonsense-mediated decay established a loss-of-function mechanism reducing protein and disrupting H2AK119Ub1 control.

    Evidence RT-PCR/mRNA NMD analysis, ASXL3 protein western, and H2AK119Ub1 western in BRS patient-derived fibroblasts; domain annotation (ASXN, ASXM, PHD)

    PMID:26647312

    Open questions at the time
    • Functional contribution of individual ASXN/ASXM/PHD domains untested
    • Dominant-negative vs haploinsufficiency not distinguished
    • Neurodevelopmental phenotype link inferred, not modeled
  4. 2017 Medium

    Whether ASXL3 sustains proliferative programs in tumors was open; silencing experiments showed it is required for proliferation, clonogenicity, and malignant growth in lung-derived cells.

    Evidence siRNA/shRNA knockdown with proliferation, clonogenicity, teratoma, and xenograft assays in iPSCs and SCLC lines

    PMID:28935813

    Open questions at the time
    • Mechanistic link to PR-DUB or PRC2 placement remains abstract-level
    • Direct target genes not defined here
    • Single lab
  5. 2020 High

    It was unknown how ASXL3 connected the BAP1 complex to active transcription; identifying a direct BRD4 ET-domain interaction defined ASXL3 as an adaptor maintaining BRD4 enhancer occupancy and H3K27Ac.

    Evidence SEC, mass spectrometry, co-IP/western for the BBM-ET interaction plus BRD4/H3K27Ac ChIP-seq and RNA-seq under ASXL3 depletion in SCLC-A cells

    PMID:32669118

    Open questions at the time
    • Structural detail of the BBM-ET interface not resolved
    • Whether BRD4 bridging is generalizable beyond SCLC-A untested
    • Interplay between deubiquitination and BRD4 recruitment unresolved
  6. 2022 Medium

    Whether the BAP1/ASXL3/BRD4 axis is pharmacologically tractable was untested; BAP1 catalytic inhibition was shown to degrade the ASXL3 scaffold and repress neuroendocrine programs, identifying a therapeutic vulnerability.

    Evidence iBAP-II treatment with ASXL3 protein western, viability assays, and in vivo xenograft tumor growth in SCLC

    PMID:35194152

    Open questions at the time
    • Mechanism linking BAP1 catalysis to ASXL3 stability not defined
    • Abstract-level description
    • Off-target effects of iBAP-II not excluded
  7. 2023 Low

    How ASXL3 mutations impair cardiac cells was unknown; a compound-heterozygous model implicated an lncRNA-FGFR2-Ras/ERK axis controlling proliferation and apoptosis.

    Evidence lncRNA/mRNA-seq, CCK8/flow cytometry, and lncRNA-silencing/FGFR2-rescue experiments in HL-1 cardiomyocytes

    PMID:37435360

    Open questions at the time
    • Single cell-line model with mechanism inferred from mutant overexpression
    • Direct chromatin mechanism connecting ASXL3 to the lncRNA not shown
    • Relevance to human cardiac disease unconfirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASXL3's distinct activities — PR-DUB deubiquitination, BRD4 enhancer bridging, and nuclear-receptor corepression — are coordinated on chromatin and which is decisive for neurodevelopmental versus oncogenic outcomes remains unresolved.
  • No structural model of ASXL3 in any complex
  • Domain-resolved contributions to each function untested
  • No in vivo model integrating chromatin and disease phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
BAP1BRD4HP1ALSD1NR1H3THRB
Complex memberships
PR-DUB

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ASXL3 physically interacts with BAP1, the catalytic subunit of the Polycomb Repressive Deubiquitination (PR-DUB) complex, and loss of ASXL3 in patient fibroblasts leads to a significant increase in histone H2AK119 mono-ubiquitination (H2AK119Ub1), demonstrating that ASXL3 is required for PR-DUB-mediated deubiquitination of H2A. Co-immunoprecipitation (Co-IP) of ASXL3 with BAP1; quantitative H2AK119Ub1 western blot in primary patient fibroblasts; transcriptome comparison by RNA-seq Human molecular genetics High 26647312
2020 ASXL3 functions as an adaptor/scaffold protein that directly bridges BRD4 to the BAP1 complex in SCLC-A cells: ASXL3 interacts with BRD4's extra-terminal (ET) domain via a novel BRD4-binding motif (BBM), and this interaction maintains chromatin occupancy of BRD4 at active enhancers; genetic depletion of ASXL3 causes genome-wide reduction of H3K27Ac levels and BRD4-dependent gene expression. Size exclusion chromatography, mass spectrometry, western blot for protein-protein interaction; ChIP-seq for BRD4 and H3K27Ac; RNA-seq; ASXL3 genetic depletion Genome medicine High 32669118
2022 Pharmacologic inhibition of BAP1 catalytic activity with iBAP-II disrupts the BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, and represses ASCL1/MYCL/E2F neuroendocrine transcriptional programs in SCLC cells, inhibiting cell viability and tumor growth in vivo. BAP1 inhibitor treatment (iBAP-II); western blot for ASXL3 protein levels; cell viability assays; in vivo xenograft tumor growth experiments Oncogene Medium 35194152
2014 ASXL3 interacts with HP1α and LSD1 and acts as a transcriptional corepressor of LXRα and TRβ: ligand-dependent physical interactions between ASXL3 and LXRα/TRβ were demonstrated, ASXL3 is recruited to LXR-response elements to suppress LXRα target gene expression, and ASXL3 overexpression reduces lipid accumulation while ASXL3 depletion increases it in Hep3B cells. GST pull-down; immunoprecipitation; chromatin immunoprecipitation (ChIP) at LXR-response elements; ASXL3 overexpression and depletion with gene expression and lipid accumulation assays Biochemical and biophysical research communications Medium 25450400
2015 ASXL3 harbors ASXN, ASXM and PHD domains (consistent with Polycomb-group scaffold function), and truncating mutations in BRS patient fibroblasts produce ASXL3 mRNA subject to nonsense-mediated decay, reducing ASXL3 protein expression and disrupting H2AK119Ub1 regulation. RT-PCR/mRNA analysis for nonsense-mediated decay; western blot for ASXL3 protein; H2AK119Ub1 western blot in patient-derived fibroblasts Human molecular genetics Medium 26647312
2017 ASXL3 silencing in lung iPSCs and SCLC cell lines inhibits proliferation, clonogenicity, and teratoma formation, and reduces malignant growth in vivo, consistent with a role for ASXL3 in sustaining stem/proliferative transcriptional programs associated with PRC2. ASXL3 siRNA/shRNA knockdown; cell proliferation and clonogenicity assays; in vivo teratoma and xenograft formation Cancer research Medium 28935813
2023 ASXL3 compound heterozygous mutations in mouse cardiomyocytes upregulate lncRNA NONMMUT063967.2, which suppresses FGFR2 expression and inhibits the Ras/ERK signaling pathway, leading to reduced cell proliferation and increased apoptosis; silencing of lncRNA NONMMUT063967.2 or overexpression of FGFR2 reverses these effects. lncRNA/mRNA sequencing; CCK8 and flow cytometry assays; qRT-PCR and western blot; lncRNA silencing and FGFR2 overexpression rescue experiments in HL-1 cells Biochemistry and biophysics reports Low 37435360

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Human molecular genetics 63 26647312
2004 Identification and characterization of ASXL3 gene in silico. International journal of oncology 60 15138607
2017 Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. Journal of medical genetics 54 28100473
2015 Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert review of proteomics 52 25835095
2020 ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. Genome medicine 51 32669118
2013 De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. BMC medical genomics 47 24044690
2016 Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. European journal of human genetics : EJHG 44 27901041
2018 A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge-Ropers syndrome. Cold Spring Harbor molecular case studies 37 29305346
2016 Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. American journal of medical genetics. Part A 30 27075689
2022 Therapeutic targeting of BAP1/ASXL3 sub-complex in ASCL1-dependent small cell lung cancer. Oncogene 26 35194152
2020 Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease. Human genetics 23 32696347
2021 Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3. American journal of medical genetics. Part A 22 34436830
2017 ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer. Cancer research 22 28935813
2019 Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay. Molecular medicine reports 16 31180560
2022 Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype. American journal of medical genetics. Part A 15 36177608
2020 Mosaicism in ASXL3-related syndrome: Description of five patients from three families. European journal of medical genetics 14 32240826
2020 Bainbridge-ropers syndrome caused by loss-of-function variants in ASXL3: Clinical abnormalities, medical imaging features, and gene variation in infancy of case report. BMC pediatrics 12 32517662
2017 Novel compound heterozygous ASXL3 mutation causing Bainbridge-ropers like syndrome and primary IGF1 deficiency. International journal of pediatric endocrinology 10 28785287
2024 ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism. Clinical genetics 9 38420660
2017 Mild prominence of the Sylvian fissure in a Bainbridge-Ropers syndrome patient with a novel frameshift variant in ASXL3. Clinical case reports 9 29445472
2014 Repression of LXRα by a novel member of additional sex comb-like family, ASXL3. Biochemical and biophysical research communications 9 25450400
2022 De novo nonsense variant in ASXL3 in a Chinese girl causing Bainbridge-Ropers syndrome: A case report and review of literature. Molecular genetics & genomic medicine 8 35276034
2018 [Bainbridge-Ropers syndrome with ASXL3 gene variation in a child and literature review]. Zhonghua er ke za zhi = Chinese journal of pediatrics 7 29429203
2018 Phenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome. Neuropsychiatric disease and treatment 6 29628764
2024 Four heterozygous de novo variants in ASXL3 identified with Bainbridge-Ropers syndrome and further dissecting published genotype-phenotype spectrum. Frontiers in neuroscience 5 39610869
2020 Novel mutation in the ASXL3 gene in a Chinese boy with microcephaly and speech impairment: A case report. World journal of clinical cases 5 33392332
2019 Novel Nonsense Mutation in ASXL3 causing Bainbridge-Ropers Syndrome. Indian pediatrics 5 31638014
2025 Speech and Language Development of Two Brothers With Bainbridge-Ropers Syndrome: Phenotypic and Bioinformatic Support for a Cerebellar ASXL3 Hypothesis. American journal of medical genetics. Part A 3 40891523
2023 ASXL3 gene mutations inhibit cell proliferation and promote cell apoptosis in mouse cardiomyocytes by upregulating lncRNA NONMMUT063967.2. Biochemistry and biophysics reports 3 37435360
2022 ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy. Neuropediatrics 3 35863334
2021 [Analysis of ASXL3 gene variant in a child with Bainbridge-Ropers syndrome]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 33751541
2021 Case report : a novel ASXL3 gene variant in a Sudanese boy. BMC pediatrics 3 34886823
2021 [A case of Bainbridge-Ropers syndrome with autism in conjunct with ASXL3 gene variant and its clinical analysis]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 34247375
2025 Paternal mosaicism in ASXL3-related bainbridge-ropers syndrome: implications for genetic counseling and prenatal diagnosis. Frontiers in pediatrics 1 40980137
2024 [Report of a child with Bainbridge-Ropers syndrome due to a novel variant of ASXL3 gene and a literature review]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 39097281
2020 [Diagnosis of Bainbridge-Ropers syndrome due to de novo ASXL3 variant by high throughput sequencing]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 32219835
2026 Correction: Case Report: Synergistic effects of an ASXL3 mutation and a 15q11.2 BP1-BP2 microdeletion in a severe neurodevelopmental phenotype. Frontiers in genetics 0 41584925
2026 ASXL3 gene variants causing Bainbridge-Ropers syndrome: clinical and genetic analysis of four Chinese patients. Frontiers in neuroscience 0 41659201
2026 Studying Familial Bainbridge-Ropers Syndrome Due to a Novel ASXL3 Germline Variant and Expanding the Clinical Spectrum. Children (Basel, Switzerland) 0 42194125
2025 A novel ASXL3 gene variant in a Chinese Boy causing Bainbridge. BMC infectious diseases 0 41146021
2025 Case Report: Synergistic effects of an ASXL3 mutation and a 15q11.2 BP1-BP2 microdeletion in a severe neurodevelopmental phenotype. Frontiers in genetics 0 41458212

Missed literature

Know a paper Affinage missed for ASXL3? Flag it for the maintainers and the community.

No submissions yet.