Affinage

ZNF280C

Zinc finger protein 280C · UniProt Q8ND82

Round 2 corrected
Length
737 aa
Mass
83.1 kDa
Annotated
2026-04-28
35 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF280C is a C2H2 zinc finger protein with dual roles in DNA damage response and epigenetic transcriptional repression. At DNA double-strand breaks and stalled replication forks, ZNF280C binds single-stranded DNA, inhibits MRE11 ssDNA association, and slows DNA end resection independently of 53BP1 and HELB, thereby repressing homologous recombination; its loss confers enhanced HR, accelerated stressed replication fork progression, and resistance to DSBs and PARP inhibition (PMID:30567999). In colorectal cancer, ZNF280C occupies chromatin regions overlapping CTCF/cohesin sites and maintains H3K27me3-mediated silencing of tumor suppressor genes by counteracting CTCF/cohesin activity, condensing cis-regulatory chromatin, and recruiting the epigenetic repressor SMCHD1, and is required for intestinal tumorigenesis in colitis-associated and Apc-deficiency mouse models (PMID:35605119).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2018 High

    The first mechanistic study answered how ZNF280C participates in the DNA damage response: it directly binds ssDNA at DSBs and stalled forks, competitively inhibits MRE11 ssDNA association, and limits DNA end resection to repress homologous recombination through a pathway independent of 53BP1 and HELB.

    Evidence Proximity-dependent biotinylation (BirA-RAD18), in vitro ssDNA binding and MRE11 competition assays, cell-based resection and HR frequency assays, genetic epistasis with 53BP1/HELB, and PARP inhibitor resistance phenotyping in human cells

    PMID:30567999

    Open questions at the time
    • Structural basis of ZNF280C ssDNA binding and MRE11 competition is unknown
    • Regulation of ZNF280C recruitment to and dissociation from damage sites has not been defined
    • Whether ZNF280C's DNA damage role contributes to its tumorigenic function is untested
  2. 2022 High

    A second study resolved ZNF280C's nuclear transcriptional function: it acts as an epigenetic repressor in colorectal cancer by maintaining H3K27me3 at tumor suppressor loci, counteracting CTCF/cohesin, and recruiting SMCHD1, establishing it as required for intestinal tumorigenesis.

    Evidence ChIP-seq for ZNF280C, H3K27me3, CTCF, and cohesin; co-immunoprecipitation of ZNF280C–SMCHD1; knockdown phenotyping (proliferation, clonogenicity, migration, xenografts); colitis-associated and Apc-deficiency mouse tumor models

    PMID:35605119

    Open questions at the time
    • Whether ZNF280C directly binds DNA at its chromatin occupancy sites through its zinc finger domains or is recruited indirectly has not been resolved
    • The relationship between ZNF280C's ssDNA-binding/DNA repair function and its chromatin silencing activity is unexplored
    • No structural or biochemical characterization of the ZNF280C–SMCHD1 interaction exists

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how ZNF280C's two described functions — ssDNA-dependent HR repression and H3K27me3-mediated transcriptional silencing — are coordinated, whether they are cell-context-dependent, and what upstream signals regulate ZNF280C activity at each site.
  • No integrative study has tested whether the DNA damage and chromatin silencing functions are separable or interdependent
  • Post-translational regulation of ZNF280C is undefined
  • No crystal or cryo-EM structure of ZNF280C or its complexes is available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2
Pathway
R-HSA-1643685 Disease 1 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
MRE11RAD18SMCHD1

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 ZNF280C (named ZPET, zinc finger protein proximal to RAD18) was identified as a DNA damage response protein using a localized proximity biotinylation approach (BirA fused to RAD18). ZPET binds single-stranded DNA (ssDNA) and localizes to DNA double-strand breaks (DSBs) and stalled replication forks. In vitro, ZPET inhibits MRE11 binding to ssDNA. In cells, ZPET delays MRE11 chromatin association after DSB formation and slows DNA end resection by binding ssDNA. This function is independent of 53BP1 and HELB. Loss of ZPET results in enhanced homologous recombination (HR), accelerated replication fork progression under stress, and increased resistance to DSBs and PARP inhibition, establishing ZPET/ZNF280C as a repressor of homologous recombination. Proximity-dependent biotinylation (BirA-RAD18 fusion), in vitro ssDNA binding assays, in vitro MRE11 competition assay, cell-based DSB resection assays, HR frequency measurement, replication fork assays, genetic epistasis (53BP1/HELB knockdown), PARP inhibitor resistance assays Genes & development High 30567999
2022 ZNF280C acts as a tumorigenic transcription factor in colorectal cancer. As a C2H2 zinc finger protein, ZNF280C occupies genomic intervals with both active and repressive chromatin states, co-localizing with CTCF and cohesin binding sites. ZNF280C is required for maintaining H3K27me3-mediated transcriptional repression at tumor suppressor gene loci. Mechanistically, ZNF280C counteracts CTCF/cohesin activities, condenses chromatin at cis-regulatory elements of H3K27me3-marked tumor suppressor genes, and recruits the epigenetic repressor SMCHD1 to these loci. Loss of ZNF280C in human CRC cells inhibits proliferation, clonogenicity, migration, xenograft growth, and liver metastasis, and is required for colitis-associated and Apc-deficiency-driven intestinal tumorigenesis in mice. ChIP-seq (H3K27me3, CTCF, cohesin, ZNF280C occupancy), co-immunoprecipitation (ZNF280C-SMCHD1 interaction), siRNA/shRNA knockdown with proliferation, clonogenicity, migration, and xenograft assays, mouse colitis-associated carcinogenesis and Apc-deficiency tumor models Proceedings of the National Academy of Sciences of the United States of America High 35605119

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of cell biology 1850 22412018
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2001 Three classes of C2H2 zinc finger proteins. Cellular and molecular life sciences : CMLS 332 11361095
2007 Sticky fingers: zinc-fingers as protein-recognition motifs. Trends in biochemical sciences 325 17210253
2008 Keep your fingers off my DNA: protein-protein interactions mediated by C2H2 zinc finger domains. Cell biochemistry and biophysics 247 18253864
2016 A High-Density Map for Navigating the Human Polycomb Complexome. Cell reports 216 27705803
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2017 Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nature communications 99 28986522
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2009 Zinc fingers as biologic redox switches? Antioxidants & redox signaling 76 19132878
2016 Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators. Cell reports 72 27880917
2020 N-Terminomics for the Identification of In Vitro Substrates and Cleavage Site Specificity of the SARS-CoV-2 Main Protease. Proteomics 70 33111431
2022 MYC multimers shield stalled replication forks from RNA polymerase. Nature 63 36424410
2020 HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137. eLife 57 32538781
2022 Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy. Nature communications 53 36057605
2017 The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing. Scientific reports 46 29044188
2019 Gain of Additional BIRC3 Protein Functions through 3'-UTR-Mediated Protein Complex Formation. Molecular cell 42 30948266
2020 Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations. American journal of human genetics 39 32891193
2022 Can Exercise Training Alter Human Skeletal Muscle DNA Methylation? Metabolites 20 35323665
2018 Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination. Genes & development 17 30567999
2022 Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci. Proceedings of the National Academy of Sciences of the United States of America 14 35605119
2024 Human transcriptome array analysis and diffusion tensor imaging in attention-deficit/hyperactivity disorder. Journal of psychiatric research 2 38412785
2025 An investigation of a hemophilia A female with heterozygous intron 22 inversion and skewed X chromosome inactivation. Frontiers in genetics 0 39834547