Affinage

ZNF207

BUB3-interacting and GLEBS motif-containing protein ZNF207 · UniProt O43670

Length
478 aa
Mass
50.8 kDa
Annotated
2026-04-28
22 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF207 (BuGZ) is a multifunctional zinc-finger protein that integrates mitotic spindle control, RNA processing, and transcriptional regulation through distinct structural domains and phase-separation behavior. Its conserved GLEBS domain binds and stabilizes Bub3, loading it onto kinetochores prior to Bub1 and BubR1 to enable spindle assembly checkpoint signaling and chromosome alignment, while its zinc-finger domain directly binds microtubules to support kinetochore–microtubule attachment (PMID:24462186, PMID:24462187, PMID:32820050, PMID:40425854). ZNF207 undergoes liquid–liquid phase separation that concentrates Aurora A kinase, promoting its activation at spindle poles and centrosomes for spindle assembly (PMID:29074706, PMID:38746663). Beyond mitosis, the zinc-finger domain functions as a U1 snRNP auxiliary factor that broadly influences alternative splicing (PMID:41475346), isoform switching governs a partnership with OCT4/SOX2/NANOG in human embryonic stem cell pluripotency and ectoderm commitment (PMID:30349051), and ZNF207 acts as a transcription factor at glycolytic gene promoters and cooperates with the SETD1A histone methyltransferase complex at chromatin (PMID:40684964, PMID:37535603).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2014 High

    Identifying BuGZ as a Bub3 chaperone resolved how free Bub3 is stabilized and loaded onto kinetochores upstream of Bub1/BubR1, filling a gap in spindle assembly checkpoint assembly logic.

    Evidence Direct binding assays, GLEBS-domain mutagenesis, RNAi, and live-cell imaging in human and Xenopus systems across two independent labs

    PMID:24462186 PMID:24462187

    Open questions at the time
    • Structural basis of the BuGZ-Bub3 GLEBS interaction unresolved
    • Whether BuGZ chaperone function is regulated by post-translational modifications unknown
  2. 2014 High

    Demonstrating that BuGZ depletion reduces kinetochore levels of Bub1, Bub1-dependent H2A phosphorylation, and Aurora B activity established BuGZ as a key upstream organizer of the kinetochore signaling hierarchy.

    Evidence RNAi knockdown with immunofluorescence and phosphorylation quantification in human cells

    PMID:24462187

    Open questions at the time
    • Direct versus indirect effects on Aurora B activity not distinguished
    • Whether BuGZ regulates Mad1/Mad2 checkpoint arm independently of Bub3 not tested
  3. 2017 High

    Showing that BuGZ coacervation concentrates Aurora A and promotes its activation in vitro and in Xenopus extracts introduced phase separation as a mechanism for mitotic kinase regulation.

    Evidence In vitro reconstitution of BuGZ coacervates with recombinant Aurora A, kinase assays, coacervation-deficient mutants, and Xenopus egg extract depletion/add-back

    PMID:29074706

    Open questions at the time
    • Physiological regulation of BuGZ coacervation in living cells not fully characterized
    • Contribution of BuGZ-Aurora A LLPS versus BuGZ-Bub3 function to overall mitotic fidelity not separated
  4. 2018 Medium

    Discovery that a specific ZNF207 isoform partners with OCT4/SOX2/NANOG revealed a non-mitotic role in stem cell pluripotency and lineage commitment via isoform switching.

    Evidence OCT4 enhancer proteomics pull-down, co-immunoprecipitation, knockdown and differentiation assays in human embryonic stem cells

    PMID:30349051

    Open questions at the time
    • Isoform-specific structures and their differential interaction surfaces with pluripotency factors not determined
    • How isoform switching is regulated at the splicing level was unresolved at this time
    • Not independently replicated
  5. 2020 High

    Temporal ordering of kinetochore recruitment—BuGZ arrives before Bub1/BubR1 via GLEBS alone—established a sequential chaperone-to-checkpoint model of kinetochore assembly.

    Evidence Live-cell kinetics, domain-mutant analysis, and size-exclusion chromatography of pre-kinetochore Bub3 complexes

    PMID:32820050

    Open questions at the time
    • Whether other GLEBS-containing proteins compete with BuGZ for Bub3 in vivo not addressed
    • Structural model of the ternary BuGZ-Bub3-kinetochore interface lacking
  6. 2023 Medium

    Finding that BuGZ/BUB3 bind the FLOS domain of SETD1A and co-occupy chromatin at promoters and enhancers connected the mitotic BuGZ–Bub3 module to interphase transcriptional regulation and leukemia cell proliferation.

    Evidence FLOS domain interaction screen, co-immunoprecipitation, ChIP-seq, domain-mutant proliferation assays

    PMID:37535603

    Open questions at the time
    • Whether BuGZ contributes to H3K4 methylation or acts independently at SETD1A targets not resolved
    • Single-lab observation, not independently replicated
  7. 2023 Medium

    Demonstrating interphase nuclear phase separation of BuGZ in Drosophila intestinal stem cells, with downstream regulation of the m6A reader YT521-B, extended the coacervation paradigm beyond mitosis to tissue-level stem cell proliferation.

    Evidence Live imaging, genetic manipulation, RNA-seq, and phase separation assays in Drosophila gut

    PMID:37872148

    Open questions at the time
    • Conservation of interphase nuclear condensation in mammalian systems not demonstrated
    • Mechanism by which m6A pathway feeds back to regulate BuGZ coacervation not fully defined
    • Single-lab study in an invertebrate model
  8. 2024 Medium

    Showing that BuGZ enhances Aurora A liquid-liquid phase separation at centrosomes and that this condensation drives centrosome maturation and separation extended the BuGZ–Aurora A axis to centrosome-specific functions.

    Evidence In vitro LLPS reconstitution, live-cell imaging, domain mutagenesis, centrosome functional assays

    PMID:38746663

    Open questions at the time
    • Quantitative contribution of BuGZ-driven LLPS versus other Aurora A activators (TPX2) not compared
    • Not independently replicated
  9. 2025 High

    Identification of Cys54 in the zinc-finger domain as the covalent target of parthenolide mapped the precise residue required for microtubule binding and kinetochore–microtubule attachment.

    Evidence Click-chemistry proteomics, quantitative mass spectrometry, Cys54 mutagenesis, kinetochore attachment assays

    PMID:40425854

    Open questions at the time
    • Whether Cys54 is a physiological redox-sensitive switch or exclusively a drug target is unknown
    • Structure of the zinc-finger–microtubule interface not determined
  10. 2025 High

    Genome-scale CRISPR-splicing screens revealed that the ZNF207 zinc-finger domain interacts with U1 snRNP components to broadly regulate alternative splicing, including clinically relevant LMNA/progerin splicing in Hutchinson-Gilford progeria cells, establishing a major non-mitotic molecular function.

    Evidence CRASP-seq, high-throughput mutagenesis, ZNF207 depletion in progeria patient fibroblasts, U1 snRNP interaction assays

    PMID:41475346

    Open questions at the time
    • Whether splicing regulation and mitotic functions are temporally segregated by cell-cycle stage not tested
    • Target RNA sequence or structural specificity of ZNF207 as splicing factor not defined
  11. 2025 Medium

    Parallel studies in hepatocellular carcinoma demonstrated direct transcriptional activation of glycolytic genes (ENO1, GAPDH) and facilitation of PRDX1 lactylation driving NRF2-mediated ferroptosis resistance, revealing convergent oncogenic mechanisms.

    Evidence ChIP-qPCR, dual-luciferase reporter assays, CRISPR screening, lactylation site mapping, NRF2 activity assays, xenografts

    PMID:40680452 PMID:40684964

    Open questions at the time
    • Whether ZNF207 directly catalyzes or scaffolds the lactylation event is unclear
    • Generalizability beyond HCC models not established
    • Single-lab studies
  12. 2025 Medium

    hnRNPA1 was identified as a trans-acting regulator of ZNF207 exon 9 skipping, providing a mechanism for isoform switching that modulates downstream PI3K/Akt/mTOR signaling.

    Evidence RIP assay, qPCR, knockdown in HCC cells

    PMID:39834948

    Open questions at the time
    • Whether hnRNPA1-dependent isoform switching also operates in stem cells to control pluripotency unknown
    • Single-lab, single-method binding evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the mitotic (Bub3 chaperone, microtubule binding, Aurora A LLPS), splicing (U1 snRNP auxiliary factor), and transcriptional functions of ZNF207 are coordinated across the cell cycle and in different cell types remains an open question.
  • No integrative study has compared isoform-specific interactomes across cell-cycle phases
  • Structural basis for multi-domain functional switching is unknown
  • In vivo genetic models (knockout mice) are not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 4 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1266738 Developmental Biology 1
Partners
AURKABUB1BUB1BBUB3HNRNPA1POU5F1SETD1ASOX2
Complex memberships
BuGZ-Bub3SETD1A complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 BuGZ/ZNF207 directly binds and stabilizes Bub3 via its conserved GLEBS (GLE2p-binding sequence) domain, and uses a separate microtubule-binding domain to enhance loading of Bub3 onto kinetochores during prometaphase, promoting chromosome alignment and metaphase-to-anaphase progression. Spemix screen, direct binding assays, RNAi knockdown, live-cell imaging, kinetochore protein loading assays Developmental cell High 24462186 24462187
2014 BuGZ/ZNF207 loss reduces Bub3 and Bub1 kinetochore levels, attenuates Bub1-dependent phosphorylation of centromeric histone H2A, and reduces kinetochore-based Aurora B kinase activity, placing BuGZ upstream of these SAC effectors. RNAi knockdown, immunofluorescence, phosphorylation assays, kinetochore protein quantification Developmental cell High 24462187
2017 BuGZ promotes Aurora A (AurA) activation in vitro; the two zinc fingers of BuGZ directly bind the kinase domain of AurA, allowing AurA to incorporate into BuGZ coacervates. BuGZ coacervation is required for AurA phosphorylation in Xenopus egg extracts, and BuGZ depletion reduces phosphorylated AurA on spindle MTs and decreases MCAK phosphorylation. In vitro kinase/activation assays, co-immunoprecipitation, Xenopus egg extract experiments, coacervation assays with mutant BuGZ, immunofluorescence The Journal of cell biology High 29074706
2020 BuGZ kinetochore localization requires only its core GLEBS domain (distinct from the requirements for Bub1 and BubR1); BuGZ localizes to kinetochores prior to BubR1 and Bub1; before kinetochore formation, Bub3 is complexed with BuGZ but not Bub1 or BubR1, indicating BuGZ stabilizes Bub3 and promotes its loading onto kinetochores to facilitate subsequent Bub1 and BubR1 recruitment. GLEBS domain mutant analysis, size-exclusion chromatography, live-cell kinetics, immunofluorescence The Journal of biological chemistry High 32820050
2018 In human embryonic stem cells, a distinct isoform of ZNF207 partners with master pluripotency transcription factors OCT4, SOX2, and NANOG to govern self-renewal and pluripotency, while simultaneously controlling commitment toward ectoderm through direct regulation of neuronal transcription factors including OTX2; distinct roles occur via isoform switching. Genome-wide proteomics/OCT4 enhancer pull-down, co-immunoprecipitation, knockdown, differentiation assays Nature communications Medium 30349051
2023 The FLOS domain of SETD1A directly binds BuGZ and BUB3; BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative enhancer regions; the GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A binding and leukemia cell proliferation. FLOS domain interaction screen, co-immunoprecipitation, ChIP-seq, domain mutant analysis, cell proliferation assays EMBO reports Medium 37535603
2023 BuGZ/ZNF207 undergoes age- and injury-associated phase separation (condensation) in Drosophila intestinal stem cell nuclei during interphase, promoting ISC proliferation; the m6A reader YT521-B acts as a transcriptional and functional downstream target; binding of the YT521-B promoter or m6A writer Ime4/Mettl14 to BuGZ controls its coacervation. Live imaging, genetic knockdown/overexpression, RNA-seq, co-immunoprecipitation, phase separation assays in Drosophila gut Nature communications Medium 37872148
2025 Parthenolide covalently binds to Cys54 of BUGZ/ZNF207 via Michael addition to its α-methylene-γ-lactone moiety; Cys54 lies within the second zinc-finger domain of the microtubule-targeting region, and this binding prevents kinetochore-microtubule attachment and accurate chromosome congression. Click-chemistry, quantitative mass spectrometry, site-directed mutagenesis, cell biology kinetochore attachment assays The EMBO journal High 40425854
2025 ZNF207's zinc-finger domain broadly impacts alternative splicing through direct interactions with U1 snRNP components; ZNF207 depletion enhances canonical LMNA splicing and decreases progerin protein levels in patient-derived progeria cells, positioning ZNF207 as a U1 snRNP auxiliary factor. CRASP-seq (CRISPR + splicing reporter sequencing), high-throughput mutagenesis, ZNF207 depletion in patient cells, interaction assays with U1 snRNP components Molecular cell High 41475346
2025 ZNF207 facilitates lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, which enhances nuclear translocation and activation of NRF2, promoting an antioxidant response that inhibits ferroptosis and drives regorafenib resistance in HCC cells. CRISPR/Cas9 screen, functional assays (knockdown, overexpression), lactylation site identification, subcellular fractionation, NRF2 activity assays Drug resistance updates Medium 40680452
2025 ZNF207 transcriptionally regulates ENO1 and GAPDH to promote aerobic glycolysis in HCC; mechanistic analysis using ChIP and dual-luciferase assays showed direct ZNF207 binding to ENO1 and GAPDH promoters. ChIP-qPCR, dual-luciferase reporter assays, knockdown/overexpression, in vivo xenograft Cellular signalling Medium 40684964
2025 hnRNPA1 binds ZNF207 mRNA and regulates exon 9 skipping, modulating ZNF207 isoform expression and downstream PI3K/Akt/mTOR pathway activity in HCC cells. RIP (RNA immunoprecipitation) assay, bioinformatics, qPCR, Western blot, knockdown experiments Frontiers in oncology Medium 39834948
2024 BuGZ interacts with Aurora-A to enhance its liquid-liquid phase separation and centrosome functions; Aurora-A condensation (mediated by conserved positive-charged IDR residues and intramolecular N-C terminal interaction) at centrosomes from prophase affects centrosome maturation, separation, spindle pole formation, and kinase activity. In vitro phase separation assays, live-cell imaging, co-immunoprecipitation, domain mutagenesis, centrosome functional assays iScience Medium 38746663

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 A microtubule-associated zinc finger protein, BuGZ, regulates mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting. Developmental cell 80 24462186
2014 BuGZ is required for Bub3 stability, Bub1 kinetochore function, and chromosome alignment. Developmental cell 68 24462187
2018 A distinct isoform of ZNF207 controls self-renewal and pluripotency of human embryonic stem cells. Nature communications 38 30349051
2017 Aurora A activation in mitosis promoted by BuGZ. The Journal of cell biology 38 29074706
2022 System analysis based on the cancer-immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma. Journal for immunotherapy of cancer 24 35246476
2023 Phase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators. Nature communications 15 37872148
2025 ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 14 40680452
2017 A Systematic RNAi Screen Reveals a Novel Role of a Spindle Assembly Checkpoint Protein BuGZ in Synaptic Transmission in C. elegans. Frontiers in molecular neuroscience 10 28553202
2022 Phylogenetic convergence of phase separation and mitotic function in the disordered protein BuGZ. Protein science : a publication of the Protein Society 9 34984754
2020 BuGZ facilitates loading of spindle assembly checkpoint proteins to kinetochores in early mitosis. The Journal of biological chemistry 9 32820050
2023 SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3. EMBO reports 8 37535603
2017 Phase separation of BuGZ promotes Aurora A activation and spindle assembly. The Journal of cell biology 8 29263080
2024 Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma. Journal of medicinal chemistry 5 38377560
2024 Aurora-A condensation mediated by BuGZ aids its mitotic centrosome functions. iScience 5 38746663
2022 A role for the mitotic proteins Bub3 and BuGZ in transcriptional regulation of catalase-3 expression. PLoS genetics 3 35666721
2019 [Expression of ZNF207 in hepatocellular carcinoma and its significance]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 3 31113916
2025 Parthenolide disrupts mitosis by inhibiting ZNF207/BUGZ-promoted kinetochore-microtubule attachment. The EMBO journal 2 40425854
2025 Transcription factor ZNF207 drives aerobic glycolysis and facilitates malignancy progression in hepatocellular carcinoma. Cellular signalling 2 40684964
2025 RNA-coupled CRISPR screens reveal ZNF207 as a regulator of LMNA aberrant splicing in progeria. Molecular cell 2 41475346
2025 Downregulation of hnRNPA1 inhibits hepatocellular carcinoma cell progression by modulating alternative splicing of ZNF207 exon 9. Frontiers in oncology 1 39834948
2026 Discovery, Optimization, and Biological Evaluation of 2-Cyano-2-(9H-xanthen-9-ylidene)acetamide Derivatives as ZNF207 Inhibitors for Anti-Glioma Therapy. Journal of medicinal chemistry 0 41854173
2025 RNA-coupled CRISPR Screens Reveal ZNF207 as a Regulator of LMNA Aberrant Splicing in Progeria. bioRxiv : the preprint server for biology 0 40568141