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ZBTB35

Annotated
2026-06-11
12 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF131 (ZBTB35) is a BTB/POZ–C2H2 zinc finger transcription factor that controls cell-cycle progression and proliferation by activating defined target genes, predominantly acting as a transcriptional activator (PMID:20303951). It recognizes a 12-bp palindromic DNA element (the Znf131 binding element) through its zinc finger domain and is imported into the nucleus via two functional NLS elements (NLS-1/BR-1 and NLS-2/BR-2) recognized by Importin-alpha3 (PMID:20303951, PMID:17306895). ZNF131 is a substoichiometric subunit of the EMSY/KDM5A/SIN3B histone-modifying complex and recruits EMSY to active, H3K4me3-marked promoters genome-wide (PMID:26841866). Its transcriptional output converges on proliferative and DNA-repair programs: it directly binds and activates the RAD51 promoter to amplify homologous-recombination repair, and it interacts with BACH1 through their respective BTB domains, an interaction that stabilizes both proteins by preventing CUL3-mediated ubiquitin-dependent degradation (PMID:39629137). ZNF131 likewise activates HAUS5 to sustain Augmin/HAUS-dependent mitotic spindle integrity and stem-cell self-renewal (PMID:28596487), and in hepatocellular carcinoma it acts downstream of YAP1 to activate PAIP1/AKT signaling and, with ZBTB33 (Kaiso), to activate SMC4, driving cell-cycle progression (PMID:38341068, PMID:38241815). In developing T and B lymphocytes ZNF131 suppresses the CDK inhibitor p21(Cip1) (and pro-apoptotic Bax/Puma in pro-B cells) to permit proliferation and lineage transitions (PMID:26136427, PMID:29750959). ZNF131 also heterodimerizes with Kaiso via their POZ domains, which represses ZNF131-mediated activation in a manner relieved by p120-catenin (PMID:20303951), and it represses ERalpha-dependent transcription by physically interacting with ERalpha to block its binding to the estrogen response element (PMID:18847501).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Low

    Establishing the domain architecture defined ZNF131 as a candidate BTB/POZ–zinc finger transcription factor and revealed isoform diversity that could modulate DNA-binding capacity.

    Evidence Molecular cloning, sequence analysis, and in situ expression analysis identifying an N-terminal BTB/POZ domain, C2H2/C2HC zinc fingers, and two intraexonically spliced transcripts

    PMID:12163020

    Open questions at the time
    • No direct functional assay of domain activity
    • Functional consequence of the zinc-finger-lacking short isoform untested
    • DNA-binding specificity not yet defined
  2. 2006 High

    Mapping two functional NLS elements and Importin-alpha3 binding explained how ZNF131 reaches the nucleus, a prerequisite for its transcriptional role.

    Evidence GFP-fusion truncation/mutant localization in HeLa cells and in vitro Importin-alpha3 binding assays

    PMID:17306895

    Open questions at the time
    • Regulation of nuclear import not addressed
    • Whether import is signal- or cell-cycle-regulated unknown
  3. 2008 Medium

    Identifying ZNF131 as a repressor of ERalpha showed it can also negatively regulate transcription by directly antagonizing another factor's DNA binding.

    Evidence ERE-luciferase reporter assay, EMSA showing ZNF131-ERalpha interaction blocks ERE binding, and pS2 expression analysis

    PMID:18847501

    Open questions at the time
    • No reciprocal co-IP or interaction-domain mapping
    • Endogenous physiological context untested
    • Conditions favoring activation vs repression undefined
  4. 2010 High

    Defining the palindromic binding element and the Kaiso/p120-catenin regulatory axis established ZNF131's intrinsic DNA-binding specificity and a mechanism for modulating its activator function.

    Evidence Y2H, GST pull-down, co-IP, EMSA, CAST, and promoter-reporter luciferase assays in epithelial and fibroblast cells

    PMID:20303951

    Open questions at the time
    • Endogenous target genes bound through the ZBE not identified
    • How p120-catenin relieves Kaiso inhibition mechanistically unclear
  5. 2015 Medium

    Conditional knockout in T cells tied ZNF131 to a concrete proliferative mechanism—suppression of p21(Cip1)—linking it to cell-cycle control during lymphocyte development.

    Evidence Stage-specific conditional knockout mice, gene expression analysis, and flow cytometry

    PMID:26136427

    Open questions at the time
    • Whether p21 is a direct ZNF131 target not established
    • Single lab
    • Mechanism of cdkn1a repression unresolved
  6. 2016 High

    Placing ZNF131 within the EMSY/KDM5A/SIN3B complex and at H3K4me3 promoters provided the chromatin-level mechanism for its genome-wide transcriptional activity.

    Evidence Quantitative interaction proteomics, ChIP-seq, and EMSY knockout/rescue

    PMID:26841866

    Open questions at the time
    • Substoichiometric nature leaves stable complex membership uncertain
    • Direct target genes co-regulated by ZNF131 and EMSY not enumerated
  7. 2017 Medium

    Two studies extended ZNF131's proliferative role to cancer: activation of HAUS5 for mitotic spindle integrity in glioblastoma stem cells, and association with the CCND1 promoter via Kaiso.

    Evidence shRNA knockdown with HAUS5 rescue, immunofluorescence, sphere/tumor assays (GSCs); ChIP at the CCND1 Kaiso binding site in HCT116/MCF7

    PMID:28596487 PMID:28882591

    Open questions at the time
    • CCND1 association is a single indirect ChIP experiment (Low confidence)
    • Whether HAUS5 is a direct ZNF131 transcriptional target not shown
  8. 2018 Medium

    B-cell conditional knockout replicated and broadened the p21-suppression mechanism, adding suppression of pro-apoptotic Bax/Puma during the pro-B to pre-B transition.

    Evidence mb1-Cre conditional knockout mice, flow cytometry, gene expression analysis

    PMID:29750959

    Open questions at the time
    • Direct vs indirect regulation of p21/Bax/Puma not distinguished
    • Single lab
  9. 2024 High

    Three studies defined direct ZNF131 target promoters (RAD51, SMC4, PAIP1) and a BACH1/CUL3 stabilization mechanism, integrating ZNF131 into DNA-repair, cell-cycle, and oncogenic signaling outputs.

    Evidence ChIP-seq/ChIP-qPCR, GST pull-down, co-IP/MS, domain mutagenesis, luciferase reporters, rescue experiments, and xenografts across HCC and other cancer models

    PMID:38241815 PMID:38341068 PMID:39629137

    Open questions at the time
    • RAD51 finding is High confidence; PAIP1 and SMC4 axes rest on single-lab Medium evidence
    • How BACH1 binding shields both proteins from CUL3 mechanistically unresolved
    • Relationship between YAP1-ZNF131 and chromatin-complex recruitment unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ZNF131 switches between transcriptional activation and repression and how its choice of target promoters is directed in different cell types.
  • No unified model linking ZBE binding, EMSY complex recruitment, and Kaiso/BACH1 heterodimerization
  • Determinants of activator vs repressor output undefined
  • No structural model of DNA or partner binding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1
Partners
BACH1CUL3EMSYESR1KPNA4ZBTB33
Complex memberships
EMSY/KDM5A/SIN3B histone-modifying complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 ZNF131 (Znf131) binds a 12-bp palindrome DNA sequence (GTCGCR-(X)n-YGCGAC, the Znf131 binding element/ZBE) via its zinc finger domain and functions as a transcriptional activator in both epithelial and fibroblast cells. Kaiso heterodimerizes with Znf131 via their respective POZ domains and negatively regulates Znf131-mediated transcriptional activation; this inhibition is relieved by co-expression of p120(ctn). Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, EMSA, CAST, competition/mutational analyses, promoter-reporter luciferase assay Experimental cell research High 20303951
2006 Znf131 nuclear localization is mediated by two functional nuclear localization signals, NLS-1 (BR-1) and NLS-2 (BR-2), within its amino acid sequence. Simultaneous mutation of both NLS-1 and NLS-2 abolishes nuclear localization. Wild-type Znf131, but not the NLS-1m/NLS-2m double mutant, preferentially interacts with the nuclear import receptor Importin-alpha3 in vitro. GFP-fusion truncation/mutant localization assays in HeLa cells, mutational analysis, in vitro Importin-alpha3 binding assay Biochimica et biophysica acta High 17306895
2008 ZNF131 represses ERalpha-mediated transcriptional activation in a dose-dependent manner. EMSA demonstrated that ZNF131 physically interacts with ERalpha and this interaction interrupts or prevents ERalpha binding to the estrogen response element (ERE). ZNF131 also suppresses expression of the ERalpha target gene pS2. High-throughput luciferase reporter assay (ERE-reporter), EMSA, pS2 gene expression analysis BMC genomics Medium 18847501
2016 ZNF131 is a substoichiometric interactor of the EMSY/KDM5A/SIN3B histone-modifying complex and recruits EMSY to a large number of active, H3K4me3-marked gene promoters. Quantitative interaction proteomics, ChIP-sequencing, EMSY knock-out and rescue experiments The Journal of biological chemistry High 26841866
2015 Znf131 is required for T cell proliferation at the double-negative to double-positive transition (coupled to pre-TCR signaling) and for effector gene activation in mature T cells upon TCR signaling. Mechanistically, Znf131 suppresses expression of the CDK inhibitor p21(Cip1) (encoded by cdkn1a), and loss of Znf131 elevates p21(Cip1) and impairs robust proliferation. Conditional knock-out mice (floxed allele, stage-specific Cre), gene expression analysis, flow cytometry Journal of immunology Medium 26136427
2017 ZNF131 promotes expression of HAUS5 (a component of the Augmin/HAUS microtubule nucleation complex) in glioblastoma stem-like cells (GSCs). ZNF131 knockdown causes mitotic arrest, centrosome fragmentation, loss of Augmin/HAUS complex on the mitotic spindle, and loss of GSC self-renewal; ectopic HAUS5 expression rescues ZNF131-knockdown viability defects. ZNF131 and HAUS5 knockdowns phenocopy each other in GSCs. shRNA knockdown, ectopic overexpression rescue, gene expression profiling, immunofluorescence, tumor formation assay, sphere formation assay Oncotarget Medium 28596487
2017 Znf131 associates with the CCND1 (Cyclin D1) promoter region encompassing the Kaiso Binding Site, suggesting the Znf131/Kaiso heterodimer co-regulates Cyclin D1 expression. Kaiso also inhibits Znf131 expression, indicating reciprocal transcriptional regulation. ChIP analysis in HCT116 and MCF7 cells, promoter association assays Biochemical and biophysical research communications Low 28882591
2018 ZNF131 is required for pro-B to pre-B cell transition; conditional knockout in pre-pro-B cells impairs pro-B cell proliferation and immunoglobulin heavy chain gene rearrangement. Mechanistically, ZNF131 suppresses expression of p21(Cip1) (CDK inhibitor) and pro-apoptotic factors Bax and Puma (p53 targets) to facilitate cell cycle progression and suppress apoptosis in pro-B cells. Conditional knock-out mice (mb1-Cre), flow cytometry, gene expression analysis Biochemical and biophysical research communications Medium 29750959
2024 ZNF131 directly binds the RAD51 gene promoter (region -668bp to -403bp) through its Zinc Finger and BTB domains, transcriptionally activating RAD51 expression. ZNF131 interacts with BACH1 via their respective BTB domains; this ZNF131-BACH1 interaction stabilizes both proteins by preventing CUL3-mediated ubiquitin degradation, and together they amplify RAD51-dependent homologous recombination repair and therapy resistance. ChIP-sequencing, GST pull-down, immunoprecipitation, liquid chromatography-tandem mass spectrometry, domain mutant analyses, luciferase reporter, mouse xenograft model Theranostics High 39629137
2024 ZNF131 transcriptionally activates PAIP1 expression (as shown by luciferase reporter assay) downstream of YAP1. YAP1 acts as an upstream activator of ZNF131 expression; ZNF131-driven PAIP1 upregulation activates AKT signaling to promote HCC cell proliferation. Luciferase reporter assay, YAP1 knockdown/overexpression, ZNF131 knockdown/overexpression, PAIP1 rescue experiment, AKT inhibitor treatment, mouse xenograft Archives of biochemistry and biophysics Medium 38341068
2024 ZNF131 binds the SMC4 promoter by interacting with ZBTB33 (Kaiso) at a ZBTB33-recognizing motif and transcriptionally activates SMC4 expression, driving cell-cycle progression in HCC cells. Enforced SMC4 overexpression partially reverses the growth-suppressive effects of ZNF131 knockdown. ChIP-qPCR, dual-luciferase reporter assay, ZNF131 knockdown with SMC4 rescue, CCK-8 and colony formation assays, xenograft model Biochemical and biophysical research communications Medium 38241815
2002 ZNF131 protein contains an N-terminal BTB/POZ domain and C-terminal C2H2 zinc fingers (including one C2HC structure), and two alternatively spliced transcripts are expressed from the ZNF131 gene due to intraexonic splicing, with the shorter isoform lacking the region encoding the first zinc finger. Molecular cloning, sequence analysis, whole-mount in situ hybridization, expression analysis Biochemical and biophysical research communications Low 12163020

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131. The Journal of biological chemistry 35 26841866
2010 Kaiso regulates Znf131-mediated transcriptional activation. Experimental cell research 21 20303951
2002 The murine BTB/POZ zinc finger gene Znf131: predominant expression in the developing central nervous system, in adult brain, testis, and thymus. Biochemical and biophysical research communications 19 12163020
2017 ZNF131 suppresses centrosome fragmentation in glioblastoma stem-like cells through regulation of HAUS5. Oncotarget 15 28596487
2008 High-throughput cell-based screening reveals a role for ZNF131 as a repressor of ERalpha signaling. BMC genomics 13 18847501
2006 Nuclear trafficking of the POZ-ZF protein Znf131. Biochimica et biophysica acta 11 17306895
2015 BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells. Journal of immunology (Baltimore, Md. : 1950) 9 26136427
2017 The POZ-ZF transcription factor Znf131 is implicated as a regulator of Kaiso-mediated biological processes. Biochemical and biophysical research communications 8 28882591
2024 ZNF131-BACH1 transcriptionally accelerates RAD51-dependent homologous recombination repair and therapy-resistance of non-small-lung cancer cells by preventing their degradation from CUL3. Theranostics 7 39629137
2024 YAP1-activated ZNF131 promotes hepatocellular carcinoma cell proliferation through transcriptional regulation of PAIP1. Archives of biochemistry and biophysics 6 38341068
2024 ZNF131 facilitates the growth of hepatocellular carcinoma by acting as a transcriptional activator of SMC4 expression. Biochemical and biophysical research communications 5 38241815
2018 A BTB-ZF protein, ZNF131, is required for early B cell development. Biochemical and biophysical research communications 3 29750959

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