Affinage

ZNF350

Zinc finger protein 350 · UniProt Q9GZX5

Length
532 aa
Mass
60.0 kDa
Annotated
2026-06-11
28 papers in source corpus 20 papers cited in narrative 20 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

ZNF350 (ZBRK1) is a KRAB-domain, eight-zinc-finger sequence-specific transcriptional repressor that nucleates a BRCA1-containing co-repressor complex to silence damage-response, angiogenic, and metabolic target genes (PMID:11090615, PMID:16843262). It binds the consensus GGGxxxCAGxxxTTT through its zinc-finger DNA-binding domain, which forms a homotetramer and engages cognate DNA even in the absence of zinc (PMID:24924633, PMID:12097288), and represses transcription through two separable modules: an N-terminal KRAB domain that acts broadly and BRCA1-independently, and a C-terminal repression domain (zinc fingers 5–8 plus the unique C-terminus) that confers BRCA1-, HDAC-, and promoter-specific repression and mediates oligomerization-dependent silencing (PMID:14660588, PMID:15496401). Acting with BRCA1, CtIP, and the corepressor KAP-1/TRIM28 (and additionally LCoR, which recruits SETDB1 and H3K9me3 chromatin marks), ZBRK1 directly represses GADD45A, ANG1, HMGA2, MMP9, and the metabolic gene GOT2, thereby restraining angiogenesis, invasion/metastasis, and tumor cell proliferation (PMID:16843262, PMID:19996286, PMID:20007691, PMID:24829459, PMID:30714292). Repression is reversed by DNA damage: UV or MMS triggers ubiquitin-proteasome degradation of ZBRK1 via a discrete 44-amino-acid degron between the KRAB and zinc-finger regions, derepressing GADD45A (PMID:14517299). ZBRK1 levels are themselves transcriptionally controlled by the RB·E2F1/CtIP/CtBP complex (PMID:20713352), and it can act outside the repressive mode, activating SCA2/ataxin-2 and VHL transcription (PMID:20926453, PMID:25749518) and being co-opted by Epstein–Barr virus, where it binds the oriLyt enhancer to promote lytic viral replication (PMID:15596820). Functional ZNF350 missense variants that weaken GADD45A repression provide a mechanistic link to breast cancer risk (PMID:29653063), and promoter hypermethylation that silences ZNF350 accelerates colon cancer cell migration (PMID:30613364).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Established ZBRK1 as a sequence-specific repressor and identified BRCA1 as its essential corepressor, defining a transcriptional arm of BRCA1 function.

    Evidence In vitro binding, co-IP, EMSA, and reporter assays on the GADD45 intron 3 element

    PMID:11090615

    Open questions at the time
    • Did not map the repression domains responsible
    • Mechanism of BRCA1 recruitment to chromatin unresolved
    • Scope of target genes beyond GADD45 unknown
  2. 2002 Medium

    Defined the ZBRK1 DNA recognition consensus by comparison with the related KRAB-ZFP SZF1, anchoring the GGGxxxCAGxxxTTT motif and KAP-1 corepressor linkage.

    Evidence PCR binding-site selection, EMSA, and reporter assays (study primarily of SZF1)

    PMID:12097288

    Open questions at the time
    • Direct ZBRK1–KAP-1 binding not demonstrated here
    • Genome-wide occupancy not assessed
  3. 2003 High

    Resolved how ZBRK1 repression is relieved after genotoxic stress, mapping a discrete 44-aa degron that drives proteasomal degradation and GADD45a derepression.

    Evidence Proteasome inhibition, polyubiquitin detection, deletion mutants, and derepression assays

    PMID:14517299

    Open questions at the time
    • E3 ligase responsible not identified
    • Signaling kinases linking damage to degron unknown
  4. 2003 High

    Dissected ZBRK1 into two functionally distinct repression modules, explaining how BRCA1-dependent and BRCA1-independent silencing coexist in one protein.

    Evidence Systematic mutagenesis, reporter assays, HDAC inhibition

    PMID:14660588

    Open questions at the time
    • Structural basis of CTRD–BRCA1 contact undefined
    • Identity of HDAC partner not specified
  5. 2004 High

    Showed ZBRK1 self-assembles into tetramers via the CTRD and that oligomerization, not DNA binding alone, drives efficient repression.

    Evidence Cross-linking, gel filtration, protein interaction and reporter assays

    PMID:15496401

    Open questions at the time
    • Stoichiometry on chromatin in vivo unresolved
    • No high-resolution oligomer structure
  6. 2005 High

    Revealed that EBV hijacks ZBRK1: it binds the oriLyt enhancer with KAP-1 and BRCA1 to enhance lytic viral replication, a non-repressive role.

    Evidence Y2H, co-IP, EMSA, immunofluorescence, ChIP, oriLyt replication assay

    PMID:15596820

    Open questions at the time
    • Mechanism by which ZBRK1 stimulates replication unclear
    • Whether host gene repression contributes not addressed
  7. 2006 High

    Demonstrated the BRCA1/CtIP/ZBRK1 trimeric complex restrains angiogenesis by repressing ANG1, connecting the complex to tumor vascularization in vivo.

    Evidence Microarray, reciprocal co-IP, ChIP, RNAi, angiogenesis assay, Brca1-deficient mouse tumors

    PMID:16843262

    Open questions at the time
    • CtIP's biochemical contribution to repression undefined
    • Direct relevance to human tumors not tested here
  8. 2009 Medium

    Extended the repressor complex to HMGA2 and MMP9, linking ZBRK1 loss to colony formation, abnormal acinar morphology, and invasion/metastasis.

    Evidence Microarray, RNAi, ChIP, soft agar, 3D morphogenesis, invasion and xenograft assays

    PMID:19996286 PMID:20007691

    Open questions at the time
    • MMP9 repression confirmed in a single tumor context
    • Whether targets share co-regulation in vivo unclear
  9. 2010 Medium

    Identified an upstream regulatory loop in which RB·E2F1/CtIP/CtBP transcriptionally represses ZBRK1, tying ZBRK1 levels to RB status and DNA-damage sensitivity.

    Evidence ChIP, reporter assays, RNAi, survival assays after UV/MMS

    PMID:20713352

    Open questions at the time
    • Physiological conditions activating this loop unclear
    • Single-lab observation
  10. 2010 Medium

    Uncovered a transcriptional-activator mode of ZBRK1, with ataxin-2 as its first co-activator upregulating SCA2.

    Evidence Y2H, co-IP, ChIP, luciferase, siRNA

    PMID:20926453

    Open questions at the time
    • Switch between repressor and activator states unexplained
    • Single-lab observation
  11. 2012 Medium

    Showed ZBRK1 represses the HIV-1 LTR in a KAP-1/TRIM28-dependent manner, broadening its viral-promoter repertoire.

    Evidence Ectopic expression, siRNA, reporter assay, ChIP

    PMID:22975076

    Open questions at the time
    • Effect on authentic proviral transcription not tested
    • Single-lab observation
  12. 2014 Medium

    Defined the chromatin-modifying machinery of the complex, placing LCoR–KAP-1–ZBRK1 at GADD45A and FGF2 with SETDB1 and H3K9me3, with depletion causing apoptosis.

    Evidence Co-IP, ChIP, siRNA, expression and viability assays

    PMID:24829459

    Open questions at the time
    • Order of factor assembly on chromatin unresolved
    • Direct SETDB1–ZBRK1 contact not shown
  13. 2014 Medium

    Characterized the isolated DNA-binding domain biophysically, showing zinc-independent tetrameric DNA binding and a non-B-DNA complex conformation.

    Evidence Recombinant protein purification, gel filtration, cross-linking, CD spectroscopy, pulldown

    PMID:24924633

    Open questions at the time
    • No crystal/cryo-EM structure of the complex
    • In vitro findings not validated in cells
  14. 2015 Medium

    Demonstrated a second activator role at VHL, where VHL bridges ZBRK1 to p300 and ZBRK1 suppresses VEGF via the VHL/HIF axis.

    Evidence Y2H, co-IP, reporter, shRNA, tumor assays

    PMID:25749518

    Open questions at the time
    • How p300 recruitment overrides repressor activity unclear
    • Single-lab observation
  15. 2017 Medium

    Connected the complex to cancer metabolism, showing BRCA1/ZBRK1 repress GOT2 to limit aspartate/α-ketoglutarate production and proliferation.

    Evidence Co-IP, ChIP, reporter, shRNA, metabolite and proliferation assays

    PMID:30714292

    Open questions at the time
    • CtIP/KAP-1 involvement at GOT2 not tested
    • Single-lab observation
  16. 2018 Low

    Provided disease and regulatory context: cancer-risk missense variants weaken GADD45A repression, promoter hypermethylation silences ZNF350 to drive migration, and ZNF121 modulates the ZBRK1/BRCA1 axis.

    Evidence Variant reporter assays; 5-aza, bisulfite/pyrosequencing, RNAi, migration assays; Y2H and co-IP

    PMID:29653063 PMID:30524945 PMID:30613364

    Open questions at the time
    • Variant effects shown only by reporter assay
    • ZNF121 interaction rests on single co-IP without reciprocal validation
    • Causal contribution to clinical phenotypes not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the BRCA1/CtIP/KAP-1 co-repressor assembly on chromatin and the molecular switch governing ZBRK1's transition between repressor and activator at different promoters remain undefined.
  • No structure of the assembled complex on DNA
  • Determinants of activator vs repressor mode unknown
  • Identity of the DNA-damage-responsive E3 ligase for the degron unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-4839726 Chromatin organization 1
Partners
ATXN2BBLF2/3BRCA1CTIPLCORTRIM28VHLZNF121
Complex memberships
ZBRK1/BRCA1/CtIP repressor complexZBRK1/KAP-1/LCoR repressor complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ZBRK1 (ZNF350) directly interacts with BRCA1 both in vitro and in vivo, binds the specific DNA sequence GGGxxxCAGxxxTTT within GADD45 intron 3, and represses GADD45 transcription in a BRCA1-dependent manner, revealing a corepressor function for BRCA1. In vitro binding assay, co-immunoprecipitation, DNA binding/EMSA, transcriptional reporter assay Molecular cell High 11090615
2003 Upon DNA damage (UV or MMS), ZBRK1 is rapidly degraded via the ubiquitin-proteasome pathway; a 44-amino-acid element between the N-terminal KRAB domain and the eight zinc fingers is sufficient for DNA damage-induced degradation; this degradation is independent of BRCA1 E3 ligase activity and is required for derepression of GADD45a. Proteasome inhibitor treatment, detection of polyubiquitinated ZBRK1, deletion mutant analysis, cell survival and GADD45a derepression assays Molecular and cellular biology High 14517299
2003 ZBRK1 contains a portable BRCA1-dependent C-terminal transcriptional repression domain (CTRD) composed of zinc fingers 5-8 plus the unique C-terminus; this CTRD functions in a BRCA1-, histone deacetylase-, and promoter-specific manner, distinguishable from the N-terminal KRAB repression domain which is BRCA1-independent and broadly active; the CTRD also modulates sequence-specific DNA binding activity. Domain deletion and point mutant analysis, transcriptional reporter assay, HDAC inhibitor treatment The Journal of biological chemistry High 14660588
2004 ZBRK1 homo-oligomerizes as a tetramer in solution through its C-terminal repression domain (CTRD); oligomerization facilitates ZBRK1-directed transcriptional repression via ZBRK1 response elements; the KRAB and CTRD domains but not DNA-binding activity are required for oligomerization-dependent repression. Protein cross-linking, gel filtration chromatography, in vitro and in vivo protein interaction assays, transcriptional reporter assay The Journal of biological chemistry High 15496401
2005 ZBRK1 interacts with the EBV replication protein BBLF2/3 and with the corepressor KAP-1; ZBRK1 binds a specific site in the EBV oriLyt enhancer; ZBRK1, KAP-1, and BRCA1 localize to EBV replication compartments and associate with oriLyt DNA; exogenous ZBRK1 increases oriLyt replication efficiency, and deletion of the ZBRK1 binding site impairs replication. Yeast two-hybrid, co-immunoprecipitation, EMSA, indirect immunofluorescence, chromatin immunoprecipitation, oriLyt replication assay Journal of virology High 15596820
2006 BRCA1, CtIP, and ZBRK1 form a trimeric repressor complex that represses angiopoietin-1 (ANG1) expression via a ZBRK1 recognition site in the ANG1 promoter; impairment of this complex upregulates ANG1, stabilizes endothelial cells and promotes angiogenesis; Brca1-deficient mouse mammary tumors show accelerated growth, vascularization, and ANG1 overexpression. Microarray analysis, co-immunoprecipitation, chromatin immunoprecipitation, RNA interference, in vitro angiogenesis assay, mouse mammary tumor model Cancer cell High 16843262
2009 ZBRK1 directly represses MMP9 transcription in cervical cancer cells; enforced ZBRK1 expression inhibits invasion and metastasis in vitro and in vivo; ZBRK1 and MMP9 levels are inversely correlated in tumor tissues. Enforced expression, shRNA knockdown, invasion assay, in vivo xenograft assay, ChIP/reporter assay Cancer research Medium 19996286
2009 ZBRK1, BRCA1, and CtIP form a repressor complex that coordinately represses HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter; depletion of any component activates HMGA2, increases colony formation and causes abnormal acinar morphology in mammary epithelial cells. Microarray, adenoviral RNAi, chromatin immunoprecipitation, soft agar assay, 3D acinar morphogenesis assay The Journal of biological chemistry High 20007691
2010 ZBRK1 activates SCA2 (ataxin-2) gene transcription through direct interaction with its gene product ataxin-2; elevated ZBRK1 increases ataxin-2 levels; ZBRK1-binding sites are present in the SCA2 promoter and validated by ChIP; ataxin-2 acts as the first identified ZBRK1 co-activator. Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, luciferase promoter assay, siRNA knockdown Human molecular genetics Medium 20926453
2010 The RB·E2F1/CtIP/CtBP complex represses ZBRK1 transcription by binding an E2F recognition sequence in the ZBRK1 promoter; loss of RB increases ZBRK1 transcript levels and sensitizes cells to UV- and MMS-induced DNA damage. Chromatin immunoprecipitation, reporter assay, RNAi, cell survival assay after DNA damage The Journal of biological chemistry Medium 20713352
2012 ZBRK1 represses HIV-1 LTR-mediated transcription; this repressor activity requires TRIM28 (KAP-1) binding; ZBRK1 is found bound to the HIV-1 LTR in vivo by ChIP. Ectopic expression, siRNA knockdown, luciferase reporter assay, chromatin immunoprecipitation FEBS letters Medium 22975076
2013 Loss of ZBRK1 leads to increased KAP1 expression, which enhances migration and invasion of cervical cancer cells; the N-terminal KRAB domain of ZBRK1 is specifically required for inhibiting metastasis and invasion by modulating KAP1 function in a transcriptionally dependent manner. Domain deletion analysis, shRNA knockdown, overexpression, in vitro migration/invasion assays, in vivo xenograft assay PloS one Medium 23991171
2014 LCoR (ligand-dependent corepressor) interacts with KAP-1, and together with ZBRK1 forms a trimeric complex on GADD45A intron and a novel FGF2 gene site; chromatin at these sites is enriched for SETDB1 and H3K9me3; depletion of ZBRK1, KAP-1, or LCoR elevates GADD45A and FGF2 expression and causes apoptotic cell death in breast epithelial cells. Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, gene expression analysis, cell viability assay Nucleic acids research Medium 24829459
2014 The purified ZBRK1 DNA-binding domain forms a homotetramer in solution and binds cognate DNA (5'GGGXXXCAGXXXTTT3') even in the absence of zinc ions; zinc ions increase protein stability; ZBRK1-DNA complex adopts a secondary structure significantly different from standard B-DNA. Recombinant protein purification, gel filtration, cross-linking, CD spectroscopy, pulldown assay Biochemical and biophysical research communications Medium 24924633
2015 ZBRK1 activates VHL gene transcription via a ZBRK1-binding site in the VHL promoter; VHL protein serves as a bridge between ZBRK1 and p300, facilitating increased ZBRK1 transcriptional activity at the VHL promoter; ZBRK1 suppresses VEGF transcription through the VHL/HIF pathway. Yeast two-hybrid, co-immunoprecipitation, reporter assay, shRNA knockdown, in vitro and in vivo tumor assays Oncotarget Medium 25749518
2018 ZNF121 physically interacts with ZBRK1 and BRCA1 (confirmed by yeast two-hybrid and co-immunoprecipitation) and suppresses expression of ANG1 and HMGA2, two established downstream targets of the ZBRK1/BRCA1/CtIP repressor complex; ZNF121 also regulates BRCA1 and ZBRK1 expression levels. Yeast two-hybrid, co-immunoprecipitation, gene expression analysis FEBS open bio Low 30524945
2018 Hypermethylation of the ZNF350 proximal promoter silences ZNF350 expression and accelerates colon cancer cell migration; ZNF350 knockdown accelerates migration while overexpression impairs it; three hyper-methylated CpG sites in the -268 to +49 bp region are responsible for basal promoter activity. 5-azacytidine treatment, global transcriptome analysis, global methylation analysis, siRNA knockdown, ZNF350 overexpression, migration assay, pyrosequencing, luciferase promoter assay Oncotarget Medium 30613364
2019 BRCA1 and ZBRK1 form a co-repressor complex that directly represses GOT2 (glutamate-oxaloacetate transaminase 2) transcription via a ZBRK1 recognition element in the GOT2 promoter; impairment of this complex upregulates GOT2, increases aspartate and alpha-ketoglutarate production, and accelerates breast cancer cell proliferation. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, shRNA knockdown, metabolite measurement, cell proliferation assay Molecular oncology Medium 30714292
2002 ZBRK1 and the hematopoietic KRAB-ZFP SZF1 recognize overlapping DNA consensus sequences (both bind GGGxxxCAGxxxTTT-like sites); SZF1 KRAB domain directly binds KAP-1 corepressor; full-length SZF1 represses a promoter containing ZBRK1 recognition sequences. PCR-based binding site selection, EMSA, in vitro binding assay, reporter assay Cancer research Medium 12097288
2018 ZNF350 missense variants L66P (rs2278420) and S501R (rs2278415) weaken the capability of ZNF350-mediated transcriptional repression of GADD45α, providing a functional mechanism for observed breast cancer risk associations. Luciferase reporter assay with variant ZNF350 constructs DNA and cell biology Low 29653063

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Molecular cell 203 11090615
2006 Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. Cancer cell 87 16843262
2003 Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Human mutation 46 12872252
2003 Degradation of transcription repressor ZBRK1 through the ubiquitin-proteasome pathway relieves repression of Gadd45a upon DNA damage. Molecular and cellular biology 45 14517299
2009 ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer. Cancer research 44 19996286
2009 Derepression of HMGA2 via removal of ZBRK1/BRCA1/CtIP complex enhances mammary tumorigenesis. The Journal of biological chemistry 42 20007691
2019 Preventing BRCA1/ZBRK1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation. Molecular oncology 41 30714292
2013 Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer. PloS one 38 23991171
2005 The Epstein-Barr virus replication protein BBLF2/3 provides an origin-tethering function through interaction with the zinc finger DNA binding protein ZBRK1 and the KAP-1 corepressor. Journal of virology 38 15596820
2003 Functional dissection of transcription factor ZBRK1 reveals zinc fingers with dual roles in DNA-binding and BRCA1-dependent transcriptional repression. The Journal of biological chemistry 35 14660588
2010 The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates SCA2 gene transcription through direct interaction with its gene product, ataxin-2. Human molecular genetics 33 20926453
2002 A common DNA-binding site for SZF1 and the BRCA1-associated zinc finger protein, ZBRK1. Cancer research 29 12097288
2012 ZBRK1 represses HIV-1 LTR-mediated transcription. FEBS letters 28 22975076
2015 ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer. Oncotarget 22 25749518
2005 The GADD45, ZBRK1 and BRCA1 pathway: quantitative analysis of mRNA expression in colon carcinomas. The Journal of pathology 22 15772983
2014 Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1. Nucleic acids research 20 24829459
2004 Altered expression of the ZBRK1 gene in human breast carcinomas. The Journal of pathology 20 14743505
2016 Functional SNP in 3'-UTR MicroRNA-Binding Site of ZNF350 Confers Risk for Age-Related Cataract. Human mutation 19 27586871
2010 RB·E2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1. The Journal of biological chemistry 18 20713352
2008 Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families. International journal of cancer 17 17764113
2004 Tetrameric oligomerization mediates transcriptional repression by the BRCA1-dependent Kruppel-associated box-zinc finger protein ZBRK1. The Journal of biological chemistry 15 15496401
2018 ZNF350 promoter methylation accelerates colon cancer cell migration. Oncotarget 12 30613364
2018 ZNF121 interacts with ZBRK1 and BRCA1 to regulate their target genes in mammary epithelial cells. FEBS open bio 7 30524945
2012 Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families. Journal of human genetics 5 23151675
2021 Correlation between ZBRK1/ZNF350 gene polymorphism and breast cancer. BMC medical genomics 4 33407485
2018 Functional Evaluation of ZNF350 Missense Genetic Variants Associated with Breast Cancer Susceptibility. DNA and cell biology 3 29653063
2024 ZNF350 gene polymorphisms promote the response to Peg-IFNα therapy through JAK-STAT signaling pathway in patients with chronic hepatitis B. Frontiers in immunology 2 39575240
2014 Tetrameric ZBRK1 DNA binding domain has affinity towards cognate DNA in absence of zinc ions. Biochemical and biophysical research communications 0 24924633

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