Affinage

GATAD2B

Transcriptional repressor p66-beta · UniProt Q8WXI9

Length
593 aa
Mass
65.3 kDa
Annotated
2026-06-10
30 papers in source corpus 11 papers cited in narrative 12 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

GATAD2B (p66beta) is a core subunit of the Mi-2/NuRD chromatin remodeling and histone deacetylase complex that mediates transcriptional repression at chromatin: it binds MBD2 within NuRD and engages the tails of all octamer histones in vitro through its conserved region 2 (CR2), an interaction abolished by histone tail acetylation, while a conserved-residue mutation disrupts MBD2-dependent repression and proper subnuclear distribution (PMID:16415179). Its CR1 and CR2 domains are required for assembly into NuRD, and disease-associated missense variants in these domains disrupt binding to NuRD partners (PMID:31949314); p66beta and its paralog p66alpha act cooperatively to enforce repression (PMID:16415179). Beyond constitutive repression, GATAD2B is recruited to Hedgehog target gene promoters by Suppressor of Fused to block Gli-mediated activation downstream of the primary cilium (PMID:25403183), and the GATAD2B-NuRD complex is recruited to DNA double-strand breaks in a transcription- and R-loop-dependent manner, where it drives histone deacetylation and chromatin condensation to establish a boundary that terminates DNA end resection and enables homologous recombination repair (PMID:38719994). GATAD2B is required in early development for zygotic genome activation, the G2/M transition, and genome integrity during pre-implantation embryogenesis (PMID:38605678), and for spindle assembly and chromosome alignment during oocyte meiosis, where its loss causes accumulation of acetylated proteins and aneuploidy (PMID:40468728). GATAD2B activity is tuned by post-translational modification—phosphorylation by MAP2K6 promotes heterochromatin loosening independent of p38 (PMID:34815549), and O-GlcNAcylation by OGT at its C-terminus protects it from ITCH-mediated ubiquitination and degradation (PMID:40136647). In cancer it acts beyond canonical repression, serving as a co-activator of Snail at G-box promoter elements to drive migration and metastasis (PMID:37380643) and supporting KRAS-mutant tumorigenesis through c-MYC pathway hyperactivation (PMID:30013058).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 High

    Established GATAD2B as a histone- and MBD2-binding subunit of NuRD that reads unmodified histone tails to mediate repression, defining its core molecular function.

    Evidence In vitro histone tail pull-downs, site-directed mutagenesis, knockdown repression assays, and subnuclear localization in cells

    PMID:16415179

    Open questions at the time
    • Structural basis of CR2-histone tail recognition not resolved
    • In vitro histone binding not shown at native chromatin
    • Genome-wide repression targets not mapped
  2. 2006 Medium

    Showed p66alpha and p66beta act cooperatively within NuRD, indicating functional interdependence of paralogous subunits rather than redundancy.

    Evidence Reciprocal siRNA knockdown with transcriptional repression readouts

    PMID:16415179

    Open questions at the time
    • Single-lab functional assay without biochemical reconstitution
    • Quantitative stoichiometry of p66alpha/p66beta in NuRD unknown
  3. 2014 High

    Connected GATAD2B to developmental signaling by showing Sufu recruits it to Hedgehog target promoters to repress Gli activation, placing NuRD repression downstream of cilium-dependent Hh signaling.

    Evidence Mass spectrometry, Co-IP, ChIP, cell-based Hh assays, and zebrafish validation

    PMID:25403183

    Open questions at the time
    • Whether full NuRD complex is recruited with GATAD2B at Hh genes not defined
    • Direct Sufu-binding interface on GATAD2B unmapped
  4. 2014 Medium

    Identified a LOX interaction via the CR2-containing domain promoting nuclear LOX accumulation, hinting at a non-canonical chaperone/localization role.

    Evidence Yeast two-hybrid screen, in vitro binding, and co-expression localization in tumor cells

    PMID:25118846

    Open questions at the time
    • Y2H plus co-localization without functional consequence established
    • No endogenous interaction or mechanism validated
  5. 2018 Medium

    Linked GATAD2B to oncogenic signaling by showing it drives KRAS-mutant lung cancer through c-MYC pathway hyperactivation, broadening its role beyond chromatin repression.

    Evidence In vivo functional screen, regulatable KRAS cell models, and c-MYC pathway evaluation

    PMID:30013058

    Open questions at the time
    • Molecular basis of GATAD2B-c-MYC interaction not detailed
    • Whether effect requires NuRD unknown
  6. 2020 Medium

    Defined CR1 and CR2 as the domains required for NuRD assembly by showing disease-associated missense variants disrupt partner binding, providing a molecular basis for GATAD2B-related pathology.

    Evidence Immunoprecipitation of in vitro-translated wild-type and mutant GATAD2B

    PMID:31949314

    Open questions at the time
    • Cellular and developmental consequences of variants not tested here
    • Which specific NuRD subunits each domain contacts not resolved
  7. 2021 Medium

    Revealed phosphoregulation of GATAD2B by MAP2K6 driving heterochromatin loosening during reprogramming, independent of canonical p38 signaling.

    Evidence Kinase substrate assays, kinase-dead epistasis, ChIP, and histone acetylation assays

    PMID:34815549

    Open questions at the time
    • Phosphosites on GATAD2B not pinpointed
    • Mechanism linking phosphorylation to reduced repression unclear
  8. 2023 Medium

    Showed GATAD2B can act as a transcriptional co-activator, enhancing Snail binding to G-box elements to promote migration genes, reversing its expected repressive role in a context-specific manner.

    Evidence Reciprocal Co-IP, ChIP, luciferase reporters, knockdown, and in vivo mouse metastasis

    PMID:37380643

    Open questions at the time
    • How a NuRD subunit switches to co-activation not mechanistically explained
    • Whether NuRD complex participates unknown
  9. 2024 High

    Established GATAD2B-NuRD as an R-loop-dependent responder at DNA double-strand breaks that condenses chromatin to bound DNA end resection and enable HR repair, defining a genome-stability function.

    Evidence ChIP, R-loop detection, chromatin fractionation, end resection and HR assays, and loss-of-function

    PMID:38719994

    Open questions at the time
    • Recruitment factor reading R-loops not identified
    • Connection to GATAD2B histone-binding CR2 not directly tested
  10. 2024 Medium

    Demonstrated GATAD2B is required for zygotic genome activation and pre-implantation development, extending its chromatin role into embryonic genome reprogramming.

    Evidence Immunofluorescence, siRNA knockdown, transcriptomics, proteomics, and live embryo imaging in mouse

    PMID:38605678

    Open questions at the time
    • Direct target genes at ZGA not defined
    • Whether DNA damage phenotype reflects the HR role unclear
  11. 2025 Medium

    Identified O-GlcNAcylation by OGT and ITCH-mediated ubiquitination as opposing modifications controlling GATAD2B stability, linking its abundance to cancer stem-cell maintenance.

    Evidence O-GlcNAcome proteomics, site mutagenesis, ubiquitination assays, and mammosphere assays

    PMID:40136647

    Open questions at the time
    • Specific O-GlcNAc and ubiquitination residues' interplay not fully mapped
    • Whether stabilization alters NuRD function not tested
  12. 2025 Medium

    Showed GATAD2B controls meiotic spindle assembly and chromosome alignment in oocytes via deacetylation-related gene regulation, connecting its repressive function to faithful chromosome segregation.

    Evidence Western blot, immunofluorescence, siRNA microinjection, live imaging, and RNA-seq reanalysis

    PMID:40468728

    Open questions at the time
    • Direct spindle-associated mechanism vs transcriptional effect not separated
    • Targets driving acetylated-protein accumulation not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GATAD2B's single biochemical identity as a NuRD histone-reader is reconciled with its context-specific co-activator role and its non-chromatin functions (LOX, c-MYC) remains unresolved.
  • No structural model of GATAD2B within NuRD
  • No unified mechanism explaining repressor-to-activator switching
  • Whether developmental and DNA-repair roles share the same complex composition unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2 R-HSA-162582 Signal Transduction 1 R-HSA-73894 DNA Repair 1
Partners
GATAD2AITCHMAP2K6MBD2MYCOGTSNAI1SUFU
Complex memberships
Mi-2/NuRD complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 p66beta (GATAD2B) interacts physically and functionally with MBD2 within the Mi-2/NuRD complex; mutation of a conserved residue abolishes MBD2 binding and disrupts MBD2-mediated transcriptional repression. p66beta also binds histone tails of all octamer histones in vitro, and this interaction is abolished by acetylation of histone tails. The conserved region 2 (CR2) of p66beta is required for histone tail interaction and wild-type subnuclear distribution. In vitro binding assays (histone tail pull-down), site-directed mutagenesis, knockdown experiments, subnuclear localization by fluorescence microscopy Nucleic acids research High 16415179
2006 p66alpha and p66beta function synergistically in the NuRD complex: knockdown of p66alpha impairs the repressive function of p66beta and vice versa, indicating cooperative activity within the complex. siRNA knockdown with transcriptional repression assays Nucleic acids research Medium 16415179
2014 p66beta (GATAD2B) physically interacts with Suppressor of Fused (Sufu) and is recruited by Sufu to promoters of Hedgehog (Hh) target genes to block Gli-mediated transcriptional activation; p66beta negatively regulates Hh signaling downstream of Patched, Smoothened, and the primary cilium. Proteomic (mass spectrometry) identification of Sufu-interacting proteins, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), cell-based Hh signaling assays, zebrafish in vivo validation Genes & development High 25403183
2014 p66beta (GATAD2B) interacts with the catalytic domain of lysyl oxidase (LOX) through its CR2-containing domain, and co-expression of p66beta with LOX promotes nuclear accumulation of LOX in tumor cells. Yeast two-hybrid library screening, in vitro binding confirmation, co-expression localization in tumor cells Cell and tissue research Medium 25118846
2018 GATAD2B promotes both pro-tumorigenic and pro-metastatic activities in KRAS-mutant lung cancer through interaction with c-MYC and hyperactivation of the c-MYC pathway. In vivo functional screen in mouse KRAS-mutant lung adenocarcinoma model, regulatable mutant KRAS human cell model, lentiviral co-expression system, mechanistic evaluation of c-MYC pathway activity Nature communications Medium 30013058
2020 Missense variants in the CR1 and CR2 conserved domains of GATAD2B disrupt its interactions with NuRD complex binding partners, establishing these domains as critical for NuRD complex assembly. Immunoprecipitation assays using in vitro transcription-translation products of wild-type and mutant GATAD2B Genetics in medicine Medium 31949314
2021 MAP2K6 (MKK6) phosphorylates GATAD2B, and this phosphorylation is required for MKK6-mediated heterochromatin loosening and elevated histone acetylation levels during somatic cell reprogramming; this activity does not depend on the canonical MKK6 target P38. Kinase phosphorylation assays identifying GATAD2B as MKK6 substrate, genetic epistasis (kinase-dead MKK6 mutant), ChIP for Sox2/Klf4 binding, histone acetylation assays Cell death and differentiation Medium 34815549
2023 p66beta (GATAD2B) acts as a co-activator of the transcription factor Snail in breast cancer cells: Snail interacts with p66beta, and p66beta enhances Snail binding affinity to G-box (5'-GGGAGG-3') cis-elements in promoters of migration-promoting genes, thereby inducing their transcription and promoting cell migration and lung metastasis. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), gene knockdown, luciferase reporter assays, in vivo metastasis assay in BALB/c mice Cell death & disease Medium 37380643
2024 The GATAD2B-NuRD complex is recruited to DNA double-strand breaks (DSBs) in a transcription- and DNA:RNA hybrid (R-loop)-dependent manner, promotes histone deacetylation and chromatin condensation at DSBs, establishes a spatial boundary between open and closed chromatin, and is required for correct termination of DNA end resection; loss of GATAD2B-NuRD leads to chromatin hyperrelaxation, extended DNA end resection, and homologous recombination repair failure. ChIP, DNA damage assays, R-loop detection, chromatin fractionation, end resection assays, HR repair assays, genetic loss-of-function experiments The EMBO journal High 38719994
2024 GATAD2B shows specific nuclear localization from the late 2-cell stage to the 8-cell stage in mouse embryos; depletion of GATAD2B impairs zygotic genome activation (ZGA), inhibits cell cycle G2/M phase transition, increases DNA damage at the morula stage, and reduces blastocyst formation, indicating GATAD2B is required for pre-implantation embryonic development. Immunofluorescence localization, siRNA knockdown, transcriptome analysis, proteomic analysis, live-embryo imaging, MERVL expression as ZGA marker Cell proliferation Medium 38605678
2025 GATAD2B is O-GlcNAcylated by OGT at its C-terminus; this modification protects GATAD2B from ubiquitination and proteasomal degradation. ITCH was identified as a novel E3 ubiquitin ligase for GATAD2B. O-GlcNAcylation-dependent stabilization of GATAD2B promotes breast cancer stem-like cell (CSC) maintenance, mammosphere formation, and drug resistance. Proteomics/O-GlcNAcome analysis identifying GATAD2B as OGT substrate, site-directed mutagenesis of O-GlcNAc sites, ubiquitination assays, genetic knockdown/overexpression, mammosphere formation assays Cells Medium 40136647
2025 GATAD2B regulates spindle assembly during oocyte meiosis: GATAD2B protein is stably expressed during oocyte meiosis with increased levels at MII; knockdown causes abnormal spindle assembly, chromosome misalignment, MI block, abnormal microtubule organizing center distribution, and aneuploidy, associated with downregulation of deacetylation-related genes and abnormal accumulation of acetylated proteins. Western blot, immunofluorescence, siRNA microinjection knockdown, live-cell imaging, spindle/DNA staining, RNA-seq reanalysis Animal bioscience Medium 40468728

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic acids research 67 16415179
2013 GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila. Journal of medical genetics 58 23644463
2018 In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer. Nature communications 42 30013058
2014 Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling. Genes & development 39 25403183
2020 GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder. Genetics in medicine : official journal of the American College of Medical Genetics 23 31949314
2017 Novel GATAD2B loss-of-function mutations cause intellectual disability in two unrelated cases. Journal of human genetics 15 28077840
2014 Nuclear translocation of lysyl oxidase is promoted by interaction with transcription repressor p66β. Cell and tissue research 15 25118846
2018 A novel mutation in the GATAD2B gene associated with severe intellectual disability. Brain & development 13 30482549
2017 1q21.3 deletion involving GATAD2B: An emerging recurrent microdeletion syndrome. American journal of medical genetics. Part A 13 28211977
2020 Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND). European journal of medical genetics 12 32688057
2024 The GATAD2B-NuRD complex drives DNA:RNA hybrid-dependent chromatin boundary formation upon DNA damage. The EMBO journal 11 38719994
2021 MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening. Cell death and differentiation 11 34815549
2018 Intellectual disability due to monoallelic variant in GATAD2B and mosaicism in unaffected parent. American journal of medical genetics. Part A 9 30346093
2024 Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning. Translational psychiatry 8 38238293
2023 GATA zinc finger protein p66β promotes breast cancer cell migration by acting as a co-activator of Snail. Cell death & disease 8 37380643
2019 GATAD2B-related intellectual disability due to parental mosaicism and review of literature. Clinical dysmorphology 7 31205050
2024 GATAD2B is required for pre-implantation embryonic development by regulating zygotic genome activation. Cell proliferation 5 38605678
2019 GATAD2B Gene Microdeletion Causing Intellectual Disability Autosomal Dominant Type 18: Case Report and Review of the Literature. Molecular syndromology 5 31602190
2021 Establishment of a CRISPR/Cas9-mediated GATAD2B homozygous knockout human embryonic stem cell line. Stem cell research 4 34749018
2025 GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance. Cells 3 40136647
2025 MiR-138 reprograms dental pulp stem cells into GABAergic neurons via the GATAD2B/MTA3/WNTs axis for stroke treatment. Biomaterials 3 40803231
2025 GATAD2B-related developmental and epileptic encephalopathy (DEE): Extending the epilepsy phenotype and a literature appraisal. Epilepsia open 2 39976362
2024 Psilostachyin C reduces malignant properties of hepatocellular carcinoma cells by blocking CREBBP-mediated transcription of GATAD2B. Functional & integrative genomics 2 38600341
2024 Identification of t(X;1)(q28;q21) generating a novel GATAD2B::MTCP1 gene fusion in CMML and its persistence during progression to AML. Hematology (Amsterdam, Netherlands) 2 39696784
2021 Tissue-specific DNase I footprint analysis confirms the association of GATAD2B Q470* variant with intellectual disability. Journal of genetics 2 34470925
2025 A Novel GATAD2B Frameshift Variant Causes GATAD2B-Associated Neurodevelopmental Disorder with Camptodactyly. Molecular syndromology 1 40371175
2025 Novel Intragenic Duplication of GATAD2B in a Patient With GAND. American journal of medical genetics. Part A 1 40770973
2025 GATAD2B promotes ovarian cancer malignant progression via MYC/CD47 Axis. Translational oncology 1 41389672
2025 GATAD2B regulates spindle assembly by affecting protein deacetylation during oocyte meiotic maturation. Animal bioscience 0 40468728
2023 Uterine tumor resembling high-grade endometrial mesenchymal sarcoma with GATAD2B-MMRN1 fusion. International journal of clinical and experimental pathology 0 37818386

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