Affinage

ASXL3

Putative Polycomb group protein ASXL3 · UniProt Q9C0F0

Length
2248 aa
Mass
241.9 kDa
Annotated
2026-04-28
40 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASXL3 is an epigenetic scaffold protein that functions within the Polycomb repressive deubiquitination (PR-DUB) complex by partnering with the deubiquitinase BAP1 to remove mono-ubiquitin from histone H2AK119, thereby regulating Polycomb-mediated transcriptional programs (PMID:26647312). ASXL3 also bridges BRD4 to the BAP1 complex at active enhancers via a BRD4-binding motif that engages BRD4's extra-terminal domain, maintaining BRD4 chromatin occupancy and H3K27 acetylation at enhancer elements critical for neuroendocrine lineage gene expression in small cell lung cancer (PMID:32669118, PMID:35194152). Additionally, ASXL3 acts as a ligand-dependent corepressor of nuclear receptors LXRα and TRβ through interactions with HP1α and LSD1, repressing lipid-metabolic target genes (PMID:25450400). Truncating mutations in ASXL3 cause Bainbridge-Ropers syndrome, a neurodevelopmental disorder, and loss of ASXL3 function results in elevated H2AK119Ub1 and dysregulated transcription (PMID:26647312).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 Low

    Identification of ASXL3 as the third human homolog of Drosophila Asx established a new candidate epigenetic regulator but left its molecular function entirely uncharacterized.

    Evidence Bioinformatic assembly of ASXL3 from ESTs with domain annotation (ASXN, ASXM, PHD)

    PMID:15138607

    Open questions at the time
    • No functional data; protein existence inferred computationally
    • No interaction partners identified
    • No expression or localization data
  2. 2014 Medium

    Demonstration that ASXL3 interacts with HP1α, LSD1, and ligand-bound nuclear receptors LXRα/TRβ to repress LXR target genes and lipid accumulation established ASXL3 as a ligand-dependent transcriptional corepressor.

    Evidence GST pull-down, Co-IP, ChIP at LXR-response elements, and lipid accumulation assays in Hep3B cells

    PMID:25450400

    Open questions at the time
    • Single lab/single cell line; not replicated independently
    • Physiological relevance of ASXL3 corepressor function in lipid metabolism in vivo not tested
    • Structural basis of nuclear receptor interaction not resolved
  3. 2015 High

    Showing that ASXL3 is required for BAP1-mediated deubiquitination of H2AK119 defined its core chromatin-regulatory function and linked its loss to elevated H2AK119Ub1 and the Bainbridge-Ropers syndrome phenotype.

    Evidence Co-IP of ASXL3–BAP1 in patient fibroblasts; quantification of H2AK119Ub1 by western blot; RNA-seq transcriptome comparison

    PMID:26647312

    Open questions at the time
    • Genome-wide binding sites of the ASXL3–BAP1 complex not mapped
    • Whether ASXL3 contributes distinct genomic targeting versus ASXL1/ASXL2 not resolved
  4. 2020 High

    Discovery that ASXL3 bridges BRD4 to the BAP1 complex at active enhancers via a BRD4-binding motif revealed a second major function: maintaining BRD4 chromatin occupancy and H3K27Ac at lineage-specific enhancers in SCLC.

    Evidence SEC, mass spectrometry, ChIP-seq, and RNA-seq in human and mouse SCLC cells with ASXL3 genetic depletion

    PMID:32669118

    Open questions at the time
    • Whether the BRD4-bridging function operates outside SCLC lineages not established
    • Structural detail of the BBM–ET domain interface not available
    • Relative contribution of deubiquitinase versus BRD4-tethering activities to enhancer maintenance unclear
  5. 2022 High

    Pharmacologic inhibition of BAP1 catalytic activity was shown to destabilize ASXL3 protein, collapsing the BAP1/ASXL3/BRD4 axis and suppressing SCLC tumor growth, establishing the therapeutic tractability of this pathway.

    Evidence BAP1 inhibitor (iBAP-II) treatment with western blot for ASXL3 degradation, ChIP-seq, RNA-seq, cell viability, and in vivo xenograft assays

    PMID:35194152

    Open questions at the time
    • Mechanism by which BAP1 inhibition triggers ASXL3 degradation (proteasomal vs. other pathway) not defined
    • Selectivity of iBAP-II across ASXL family members not fully characterized
  6. 2023 Medium

    ASXL3 mutations were linked to impaired cardiomyocyte proliferation and increased apoptosis via a lncRNA–FGFR2–Ras/ERK axis, extending functional consequences of ASXL3 loss to cardiac biology.

    Evidence lncRNA/mRNA sequencing, proliferation/apoptosis assays, and rescue experiments in mouse HL-1 cardiomyocytes

    PMID:37435360

    Open questions at the time
    • Mouse cardiomyocyte cell line only; not validated in primary human cardiomyocytes or in vivo cardiac models
    • Whether this lncRNA pathway is direct or secondary to H2AK119Ub1 changes unknown
    • Relevance to congenital heart defects in Bainbridge-Ropers syndrome patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include how ASXL3 achieves locus-specific genomic targeting versus its paralogs ASXL1 and ASXL2, the structural basis of its multivalent scaffold interactions, and whether its BRD4-bridging role extends to non-neuroendocrine lineages.
  • No genome-wide comparison of ASXL1/2/3 chromatin binding
  • No high-resolution structure of ASXL3 in complex with BAP1 or BRD4
  • Tissue-specific functions beyond SCLC and cardiomyocytes largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
BAP1BRD4HP1ALSD1NR1H3THRB
Complex memberships
BAP1/ASXL3/BRD4PR-DUB (BAP1-ASXL3)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ASXL3 was identified as the third member of the human ASXL family, encoding a protein with ASXN, ASXM, and PHD domains, representing a human homolog of Drosophila additional sex combs (asx) gene involved in Polycomb group-mediated transcriptional regulation. Bioinformatic/in silico identification and cDNA assembly from ESTs International journal of oncology Low 15138607
2015 ASXL3 interacts with BAP1 (a histone H2A deubiquitinase) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex, and loss of ASXL3 leads to a significant increase in H2AK119 mono-ubiquitination (H2AK119Ub1), establishing ASXL3 as required for PR-DUB-mediated deubiquitination at H2AK119. Co-immunoprecipitation in patient fibroblasts; western blot quantification of H2AK119Ub1 in ASXL3 patient vs. control fibroblasts; transcriptome comparison by RNA-seq Human molecular genetics High 26647312
2015 ASXL3 functions as an epigenetic scaffold for BAP1, EZH2, NCOA1, nuclear receptors, and WTIP; the ASXM2 domain mediates binding to androgen receptor and estrogen receptor α, while the PHD finger interacts with WTIP LIM domains. Functional proteomics review synthesizing Co-IP and domain interaction data; phylogenetic analysis of PHD fingers Expert review of proteomics Low 25835095
2014 ASXL3 interacts with HP1α and LSD1, and ligand-dependently interacts with nuclear receptors LXRα and TRβ, leading to transcriptional repression of LXRα target genes and downregulation of lipid accumulation. GST pull-down and co-immunoprecipitation; overexpression and depletion experiments in Hep3B cells; ChIP at LXR-response elements; lipid accumulation assay Biochemical and biophysical research communications Medium 25450400
2020 ASXL3 physically interacts with BRD4's extra-terminal (ET) domain via a novel BRD4-binding motif (BBM), acting as an adaptor protein that bridges BRD4 to the BAP1 complex and maintains BRD4 chromatin occupancy at active enhancers in SCLC; genetic depletion of ASXL3 causes genome-wide reduction of H3K27Ac and BRD4-dependent gene expression. Size exclusion chromatography; mass spectrometry; western blot; ChIP-seq; RNA-seq in human and mouse SCLC cells; genetic depletion (shRNA/CRISPR) Genome medicine High 32669118
2022 Pharmacologic inhibition of BAP1 catalytic activity disrupts the BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, thereby repressing neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling, inhibiting SCLC cell viability, and reducing tumor growth in vivo. BAP1 inhibitor (iBAP-II) treatment; western blot for ASXL3 protein degradation; ChIP-seq; RNA-seq; cell viability assays; in vivo xenograft tumor growth assays Oncogene High 35194152
2023 ASXL3 mutations inhibit cardiomyocyte proliferation and promote apoptosis by upregulating lncRNA NONMMUT063967.2, which suppresses FGFR2 expression and inhibits the Ras/ERK signaling pathway in mouse HL-1 cardiomyocytes. lncRNA/mRNA sequencing of mouse heart tissue; CCK8 and flow cytometry for proliferation/apoptosis; qRT-PCR and western blot for Fgfr2 and Ras/ERK pathway; lncRNA silencing rescue experiments Biochemistry and biophysics reports Medium 37435360

Source papers

Stage 0 corpus · 40 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 61 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 53 28100473
2020 ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. Genome medicine 51 32669118
2015 Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert review of proteomics 51 25835095
2013 De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. BMC medical genomics 46 24044690
2016 Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. European journal of human genetics : EJHG 42 27901041
2018 A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge-Ropers syndrome. Cold Spring Harbor molecular case studies 36 29305346
2016 Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. American journal of medical genetics. Part A 29 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
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
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 20 34436830
2019 Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay. Molecular medicine reports 15 31180560
2022 Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype. American journal of medical genetics. Part A 13 36177608
2020 Mosaicism in ASXL3-related syndrome: Description of five patients from three families. European journal of medical genetics 13 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
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
2024 ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism. Clinical genetics 8 38420660
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
2019 Novel Nonsense Mutation in ASXL3 causing Bainbridge-Ropers Syndrome. Indian pediatrics 5 31638014
2024 Four heterozygous de novo variants in ASXL3 identified with Bainbridge-Ropers syndrome and further dissecting published genotype-phenotype spectrum. Frontiers in neuroscience 4 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 4 33392332
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
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
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 2 40891523
2022 ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy. Neuropediatrics 2 35863334
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
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
2025 Paternal mosaicism in ASXL3-related bainbridge-ropers syndrome: implications for genetic counseling and prenatal diagnosis. Frontiers in pediatrics 0 40980137
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