Affinage

ZNF827

Zinc finger protein 827 · UniProt Q17R98

Length
1081 aa
Mass
119.2 kDa
Annotated
2026-06-11
12 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF827 is a C2H2 zinc-finger protein that couples chromatin remodeling to genome maintenance and gene-expression programs across telomere biology, DNA replication stress, and cell-state transitions (PMID:25150861, PMID:35941369, PMID:38472229). At alternative-lengthening-of-telomeres (ALT) telomeres, nuclear-receptor-bound ZNF827 recruits the NuRD chromatin-remodeling and histone-deacetylation complex through an N-terminal RRK motif, driving shelterin displacement, telomeric chromatin hypoacetylation, enhanced telomere-telomere interactions, and assembly of a homologous-recombination platform required for ALT cell viability (PMID:25150861); the NuRD subunit RBBP4 engages the first 14 residues of ZNF827 through a negatively charged electrostatic channel (PMID:30045876). In the context of replication stress, ZNF827 binds single-stranded DNA and associates with RPA via two clusters of C2H2 zinc-finger motifs, accumulating at stalled forks and damage sites to activate ATR and promote HR-mediated repair, such that its loss impairs replication initiation and sensitizes cancer cells to topotecan (PMID:38472229). During epithelial-to-mesenchymal transition, ZNF827 is strongly induced and recruits HDAC1 to slow RNA polymerase II progression and reprogram co-transcriptional splicing of EMT regulators, a function required for brain development and breast cancer metastasis (PMID:35941369). ZNF827 also acts as a broad transcriptional regulator in vascular smooth muscle cells and fibroblasts, where its depletion dysregulates macroautophagy and insulin-signaling genes (PMID:41983892).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2014 High

    Established how ALT telomeres are epigenetically remodeled by identifying ZNF827 as the adaptor that brings the NuRD complex to telomeres downstream of nuclear receptors.

    Evidence Co-IP, N-terminal RRK motif domain mapping, ChIP, telomere-interaction assays, and siRNA loss-of-function with viability readout in ALT cells

    PMID:25150861

    Open questions at the time
    • Did not resolve the atomic basis of the ZNF827-NuRD contact
    • Mechanism linking chromatin hypoacetylation to HR protein recruitment not fully defined
  2. 2015 Medium

    Synthesized how NuRD-ZNF827 interactions provide a physical platform for HR protein recruitment enabling template-driven telomere synthesis in ALT.

    Evidence Review/synthesis of prior protein-protein interaction and HR recruitment data

    PMID:26581522

    Open questions at the time
    • Secondary synthesis rather than new primary data
    • Order of events from chromatin remodeling to strand exchange not directly tested
  3. 2018 High

    Defined the structural basis of the ZNF827-NuRD interface, showing RBBP4 binds the ZNF827 N-terminal 14 residues through a negatively charged channel.

    Evidence Crystal structure of RBBP4 bound to the ZNF827 N-terminal peptide with mutagenesis of binding residues and telomere recruitment assays

    PMID:30045876

    Open questions at the time
    • Disrupting RBBP4 binding was insufficient to reduce ALT activity, indicating redundant recruitment routes
    • Contribution of other NuRD subunits to ZNF827 engagement not resolved
  4. 2020 Low

    Placed ZNF827 protein within an mRNP complex linked to neuronal gene expression, hinting at a post-transcriptional/RNA-associated context.

    Evidence RNA immunoprecipitation/mRNP identification and circRNA knockdown with gene-expression readout

    PMID:33174841

    Open questions at the time
    • Single RIP experiment; mechanistic role of the protein itself not resolved
    • Direct RNA binding by ZNF827 not demonstrated
  5. 2022 High

    Revealed a distinct ZNF827 function in cell-state transitions: recruiting HDAC1 to slow RNA Pol II and reprogram splicing of EMT regulators in brain development and metastasis.

    Evidence Loss-of-function with phenotypes, ZNF827-HDAC1 Co-IP, RNA Pol II ChIP, splicing analysis, and in vivo brain development and breast cancer metastasis models

    PMID:35941369

    Open questions at the time
    • Genomic targeting specificity of ZNF827 at EMT loci not defined
    • Relationship between the telomeric NuRD function and the HDAC1 splicing function unclear
  6. 2024 High

    Identified ZNF827 as an ssDNA/RPA-binding factor that operates in the replication-stress response, connecting it to ATR signaling and HR repair.

    Evidence In vitro ssDNA binding, RPA Co-IP, C2H2 zinc-finger cluster mutagenesis, damage-site imaging, ATR activation, HR and replication-initiation assays, and topotecan sensitivity

    PMID:38472229

    Open questions at the time
    • How ZNF827 is recruited to forks relative to RPA loading not fully ordered
    • Whether the same zinc-finger clusters mediate chromatin/telomere functions untested
  7. 2026 Medium

    Extended ZNF827 to vascular biology as a broad gene-expression regulator and linked a SCAD-risk variant to its expression.

    Evidence siRNA knockdown in iPSC-derived SMCs/fibroblasts with transcriptomics, plus reporter assays for variant activity and NF1 binding

    PMID:41983892

    Open questions at the time
    • Direct ZNF827 targets in SMCs not identified
    • Causal mechanism connecting the eQTL variant to vascular disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how ZNF827's distinct activities—NuRD/HDAC1 chromatin recruitment, ssDNA/RPA binding, and splicing/transcriptional control—are functionally integrated or context-switched within a single protein.
  • No structural or regulatory model coordinating its multiple functions
  • DNA sequence specificity of the C2H2 array not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1
Partners
HDAC1RBBP4RPA
Complex memberships
NuRD complexcircZNF827 mRNP complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Nuclear receptors bound to ALT telomeres recruit ZNF827, which in turn recruits the NuRD (nucleosome remodeling and histone deacetylation) complex via binding to an N-terminal RRK motif within ZNF827. This NuRD-ZNF827 recruitment results in decreased shelterin binding, hypoacetylation of telomeric chromatin, enhanced telomere-telomere interactions, and recruitment of HR proteins, and is critically important for ALT cell viability and proliferation. Co-immunoprecipitation, domain mapping (N-terminal RRK motif), chromatin immunoprecipitation, telomere-specific assays, loss-of-function (siRNA knockdown) with viability/proliferation readout Nature structural & molecular biology High 25150861
2018 The NuRD subunit RBBP4 binds to the N-terminal 14 amino acids of ZNF827 through a negatively charged channel via electrostatic interactions. Disruption of the specific RBBP4 residues required for this interaction prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. Crystal structure of RBBP4 bound to ZNF827 N-terminal peptide; mutagenesis of RBBP4 binding residues; telomere recruitment assays The Biochemical journal High 30045876
2015 NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins as part of the ALT mechanism, enabling strand exchange and template-driven DNA synthesis. Review/synthesis drawing on experimental data from prior studies; protein-protein interaction and HR recruitment assays described Nature structural & molecular biology Medium 26581522
2022 ZNF827 is strongly induced during epithelial-to-mesenchymal transition (EMT) and is required for EMT in brain development and breast cancer metastasis. Mechanistically, ZNF827 recruits HDAC1 for epigenetic modulation of distinct genomic loci, slowing RNA polymerase II progression and altering splicing of genes encoding key EMT regulators in cis, thereby orchestrating large-scale remodeling of the splicing landscape. Loss-of-function (knockdown/knockout) with molecular and phenotypic readouts; co-immunoprecipitation of ZNF827-HDAC1 complex; RNA Pol II ChIP; splicing analysis; in vivo brain development and breast cancer metastasis models Nature cell biology High 35941369
2024 ZNF827 is a single-stranded DNA (ssDNA) binding protein that associates with RPA through concurrent binding to ssDNA intermediates; these interactions depend on two clusters of C2H2 zinc finger motifs within ZNF827. ZNF827 accumulates at stalled replication forks and DNA damage sites, activates ATR, promotes homologous recombination-mediated DNA repair, and its depletion inhibits replication initiation and sensitizes cancer cells to topotecan. In vitro ssDNA binding assays; Co-immunoprecipitation with RPA; domain mutagenesis (C2H2 zinc finger cluster mutations); immunofluorescence at stalled forks/damage sites; ATR activation assays; HR repair assays; replication initiation assays; cell viability assays with topotecan Nature communications High 38472229
2020 The ZNF827 protein is part of the mRNP complex associated with circZNF827; knockdown of circZNF827 deregulates neuronal gene expression (including upregulation of NGFR), suggesting functional co-evolution of the circRNA and the protein encoded by its linear pre-mRNA host. (Note: this finding pertains to ZNF827 protein participation in an mRNP complex, not to circZNF827 itself.) RNA immunoprecipitation / mRNP complex identification; circRNA knockdown with gene expression readout eLife Low 33174841
2026 Knockdown of ZNF827 in human iPSC-derived smooth muscle cells and fibroblasts dysregulates a large number of genes enriched in macroautophagy and insulin signaling pathways, indicating ZNF827 acts as a broad regulator of gene expression in vascular SMCs and fibroblasts. A SCAD-risk intronic variant (rs13128814-A) increases transcriptional activity and preferentially binds NF1 transcription factors, with the variant colocalizing with a ZNF827 eQTL in artery tissues. siRNA knockdown in iPSC-derived SMCs and fibroblasts with transcriptomic readout; reporter assay for variant transcriptional activity; in silico NF1 binding prediction confirmed by reporter assay Clinical science (London, England : 1979) Medium 41983892

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature genetics 456 22001757
2015 Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nature structural & molecular biology 155 26581522
2014 NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination. Nature structural & molecular biology 99 25150861
2019 Prediction and Analysis of Skin Cancer Progression using Genomics Profiles of Patients. Scientific reports 51 31673075
2020 circZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation. eLife 43 33174841
2020 Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors. JACC. CardioOncology 42 34396283
2022 A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development. Nature cell biology 23 35941369
2024 ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway. Nature communications 15 38472229
2021 Genome-wide association of individual vulnerability with alcohol-associated liver disease: A Korean genome and epidemiology study. Hepatology (Baltimore, Md.) 11 34387878
2018 Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres. The Biochemical journal 11 30045876
2017 Sotos syndrome associated with Hirschsprung's disease: a new case and exome-sequencing analysis. Pediatric research 1 28399120
2026 ZNF827 pleiotropic cardiovascular risk locus involves regulation by nuclear factor-1. Clinical science (London, England : 1979) 0 41983892

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