Affinage

PHF1

PHD finger protein 1 · UniProt O43189

Length
567 aa
Mass
62.1 kDa
Annotated
2026-06-10
55 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHF1 is a chromatin-associated accessory factor of the Polycomb Repressive Complex 2 (PRC2) that couples histone-mark reading to stimulation of H3K27 trimethylation and gene silencing (PMID:18285464, PMID:23142980). It interacts with the PRC2 methyltransferase EZH2 and is specifically required for efficient H3K27me3 deposition: PHF1 depletion lowers global H3K27me3 while raising H3K27me2, and PHF1 selectively stimulates EZH2-catalyzed conversion to the trimethyl state in vitro (PMID:18285464). Its Tudor domain reads the active mark H3K36me3 through a defined recognition interface and simultaneously engages nucleosomal DNA, stabilizing a partially unwrapped nucleosome conformation that increases DNA accessibility, an effect enhanced by the adjacent N-terminal domain (PMID:23142980, PMID:24352064, PMID:28082396). A separate winged-helix domain binds DNA non-specifically, extending PRC2 residence time on chromatin and making PHF1-PRC2 a more processive H3K27 methyltransferase (PMID:29058710). PHF1 also nucleates phase-separated condensates at H3K27me3 loci that compartmentalize PRC2, DNA, and nucleosome arrays to promote transcriptional repression (PMID:37888776). Beyond Polycomb silencing, PHF1 docks chromatin-modifying machinery through its tandem PHD fingers—the N-terminal PHD recognizing PRMT5-WDR77-deposited H4R3me2s and the C-terminal PHD binding DDB1 of the CRL4B ubiquitin ligase—forming a repressive module at target genes including E-cadherin and FBXW7 (PMID:29846670). PHF1 additionally functions in the DNA damage response, being transiently recruited to double-strand breaks in a Ku70/Ku80-dependent manner to promote non-homologous end joining, and it stabilizes p53 by protecting it from MDM2-mediated ubiquitination and degradation (PMID:18385154, PMID:23150668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 High

    Established PHF1 as a functional PRC2 cofactor by showing it is required for the H3K27me2-to-me3 transition rather than for global PRC2 assembly.

    Evidence ChIP, siRNA knockdown, and in vitro HMT assay showing PHF1 specifically stimulates EZH2-catalyzed H3K27me3 and co-occupies Polycomb loci

    PMID:18285464

    Open questions at the time
    • Did not define which PHF1 domain confers the stimulatory effect
    • Mechanism of EZH2 stimulation at the catalytic level unresolved
  2. 2008 High

    Revealed an unexpected PRC2-independent role for PHF1 in DNA repair, placing it at DNA double-strand breaks.

    Evidence Laser microirradiation with Ku-dependent recruitment, X-ray sensitivity and HR reporter assays, and Co-IP with Ku70/Ku80, RAD50, SMC1, DHX9, p53

    PMID:18385154

    Open questions at the time
    • Molecular function of PHF1 at the break site unknown
    • Relationship between DSB recruitment and PRC2 activity not addressed
  3. 2012 High

    Defined the structural basis by which the PHF1 Tudor domain reads H3K36me3, linking an active chromatin mark to PRC2 regulation and DSB retention.

    Evidence 1.9-A crystal structure with H3K36me3 peptide, NMR, in vitro methyltransferase inhibition, and laser microirradiation of binding-deficient mutants

    PMID:23142980 PMID:23228662

    Open questions at the time
    • Apparent paradox of reading an active mark while promoting repression not reconciled
    • In vivo consequence of Tudor-mediated PRC2 inhibition versus stimulation unclear
  4. 2012 Medium

    Extended PHF1 function to p53 stabilization, connecting it to tumor-suppressor regulation.

    Evidence Reciprocal Co-IP, in vitro binding to the p53 C-terminal domain, ubiquitination and turnover assays, and apoptosis/growth-arrest readouts

    PMID:23150668

    Open questions at the time
    • Whether PHF1 competes directly with MDM2 not shown
    • Independence from PRC2 chromatin function not established
  5. 2013 High

    Showed the Tudor domain does more than mark-reading—it directly engages nucleosomal DNA to remodel nucleosome wrapping and increase accessibility.

    Evidence TROSY NMR and FRET on H3KC36me3 nucleosome core particles

    PMID:24352064

    Open questions at the time
    • Functional link between increased accessibility and transcriptional outcome not directly tested
    • Genomic loci affected not mapped
  6. 2017 High

    Identified two further accessibility/processivity mechanisms: the N-terminal domain cooperates with Tudor on nucleosomes, and a winged-helix domain anchors PRC2 on DNA to boost methylation processivity.

    Evidence FRET/single-molecule nucleosome assays for the NTD-Tudor module and single-molecule TIRF, crystallography, and HMT assays with DNA-binding mutants for the winged-helix domain

    PMID:28082396 PMID:29058710

    Open questions at the time
    • How accessibility-promoting and residence-extending activities are coordinated in vivo unresolved
    • Sequence determinants of locus targeting not defined
  7. 2018 Medium

    Connected PHF1's PHD fingers to two additional repressive enzymes, building a PRMT5/CRL4B/PHF1 module that links arginine methylation reading to H2AK119 ubiquitination.

    Evidence Histone peptide pull-down (N-PHD reads H4R3me2s), Co-IP of C-PHD with DDB1, ChIP-seq, and tumorigenesis assays

    PMID:29846670

    Open questions at the time
    • Direct enzymatic coupling between the modules not reconstituted
    • Generality beyond E-cadherin and FBXW7 targets not established
  8. 2023 Medium

    Proposed phase separation as the organizing principle that compartmentalizes PRC2 at H3K27me3 loci, assigning distinct functions to PHF1's domains.

    Evidence Live-cell condensate imaging, in vitro reconstitution with nucleosome arrays, and luciferase repression assays

    PMID:37888776

    Open questions at the time
    • Physiological requirement for condensate formation in vivo not tested
    • Quantitative contribution of phase separation versus domain affinities unresolved
  9. 2025 Low

    Began to resolve non-redundancy among PRC2.1 PCL paralogs, showing PHF1 directs locus-specific H3K27me3 distinct from MTF2 and PHF19 during differentiation.

    Evidence Separation-of-function mutants in human pluripotent stem cells with ChIP-seq and cardiomyocyte differentiation assays (preprint)

    PMID:bio_10.1101_2025.05.15.654236

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Mechanism distinguishing paralog locus specificity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PHF1's reading of an active H3K36me3 mark is reconciled with its role in spreading repressive H3K27me3, and how its Polycomb, DNA-repair, and p53-stabilizing activities are partitioned within a cell, remain open.
  • No unified model integrating chromatin accessibility, PRC2 processivity, and condensate formation
  • Cross-talk between PRC2 silencing and DSB/p53 functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0042393 histone binding 3 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1
Partners
DDB1EZH2KU70KU80PRMT5RAD50TP53WDR77
Complex memberships
CRL4B (CUL4B-DDB1 E3 ligase)PRC2.1PRMT5-WDR77

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 PHF1 interacts with Ezh2 (PRC2 complex) and is required for efficient H3K27 trimethylation in vivo; knockdown of PHF1 reduces global H3K27me3 levels while increasing H3K27me2, and addition of PHF1 specifically stimulates Ezh2-catalyzed H3K27me3 (but not H3K27me1/me2) in vitro. PHF1 co-occupies Ezh2-regulated loci (HoxA, MYT1, WNT1) and its depletion leads to upregulated HoxA expression and reduced Bmi-1 occupancy. Chromatin immunoprecipitation, siRNA knockdown, in vitro histone methyltransferase assay, gene expression analysis Molecular and cellular biology High 18285464
2012 The Tudor domain of human PHF1 specifically binds histone H3 trimethylated at Lys36 (H3K36me3). A 1.9-Å crystal structure of the Tudor domain in complex with H3K36me3 peptide defined the molecular mechanism of recognition. PHF1 binding to H3K36me3 inhibits PRC2-mediated methylation of H3K27 in vitro and in vivo. PHF1 is transiently recruited to DNA double-strand breaks via its Tudor domain, and mutants impaired in H3K36me3 binding show reduced retention at DSB sites. X-ray crystallography (1.9-Å), NMR, in vitro methyltransferase inhibition assay, laser microirradiation/live imaging, site-directed mutagenesis Nature structural & molecular biology High 23142980
2008 PHF1 is recruited to DNA double-strand breaks within minutes of laser microirradiation in a Ku70/Ku80-dependent manner, and dissociates within 10 min. Knockdown of PHF1 increases X-ray sensitivity and homologous recombination frequency, suggesting PHF1 promotes NHEJ. PHF1 physically interacts with Ku70/Ku80, RAD50, SMC1, DHX9, and p53. Laser microirradiation/live-cell imaging, siRNA knockdown, X-ray sensitivity assay, homologous recombination reporter assay, co-immunoprecipitation Nucleic acids research High 18385154
2012 The Tudor domains of PHF1 and PHF19 selectively bind histone H3K36me3; structural analysis revealed the molecular basis for this selectivity. The first PHD domains of PHF1 and PHF19 do not bind histone H3K4. Histone peptide binding assays, X-ray crystallography Biochemical and biophysical research communications Medium 23228662
2013 The PHF1 Tudor domain simultaneously interacts with H3K36me3 and nucleosomal DNA, stabilizing a partially unwrapped nucleosome conformation that increases DNA accessibility to regulatory proteins, as demonstrated by TROSY NMR and FRET on H3KC36me3-nucleosome core particles. TROSY NMR, FRET, nucleosome core particle binding assays Nature communications High 24352064
2017 PHF1 (Polycomblike) contains a winged-helix domain that binds DNA in a sequence-nonspecific manner. This DNA binding extends PRC2 residence time on chromatin (measured by single-molecule TIRF microscopy) and makes PHF1-PRC2 a more efficient H3K27 methyltransferase than PRC2 alone. Crystal structure of the winged-helix domain was determined and mutants disrupting DNA binding abolish the effect on PRC2 activity. Single-molecule TIRF microscopy, X-ray crystallography, in vitro methyltransferase assay, site-directed mutagenesis Nature structural & molecular biology High 29058710
2012 PHF1 directly interacts with p53 both in vivo (co-IP) and in vitro, co-localizing in the nucleus. PHF1 binds the C-terminal regulatory domain of p53. Overexpression of PHF1 elevates p53 protein level and prolongs its turnover by protecting it from MDM2-mediated ubiquitination and degradation. Knockdown of PHF1 reduces p53 protein levels and its target gene expression. PHF1 regulates p53-dependent cell growth arrest and etoposide-induced apoptosis. Co-immunoprecipitation (in vivo and in vitro), luciferase reporter assay, overexpression and siRNA knockdown, ubiquitination assay, cell growth and apoptosis assays The Journal of biological chemistry Medium 23150668
2018 The N-terminal PHD finger of PHF1 recognizes symmetric dimethylation of H4R3 (H4R3me2s) catalyzed by PRMT5-WDR77. The C-terminal PHD finger does not bind modified histones but directly interacts with DDB1, the main component of the CUL4B-Ring E3 ligase complex (CRL4B), responsible for H2AK119 mono-ubiquitination. PHF1, PRMT5-WDR77, and CRL4B reciprocally interact and collaborate as a functional unit targeting genes including E-cadherin and FBXW7. Histone peptide pull-down, co-immunoprecipitation, ChIP-seq, genome-wide target analysis, in vivo tumorigenesis assays Nucleic acids research Medium 29846670
2017 The PHF1 N-terminal domain (NTD), when attached to the Tudor domain, is partially ordered and cooperates with Tudor to dramatically enhance nucleosome DNA accessibility. PHF1 preferentially binds partially unwrapped nucleosomes and decreases DNA-protein dissociation rates, resulting in nearly an order-of-magnitude increase in DNA accessibility at H3K36me3-containing nucleosomes. FRET, single-molecule experiments, nucleosome binding assays Nucleic acids research Medium 28082396
2023 PHF1 forms phase-separated condensates at H3K27me3 loci that recruit PRC2. The N-terminal domains mediate target recognition, the chromo-like domain recruits PRC2, and the intrinsically disordered region (IDR) drives phase separation. The condensates compartmentalize PRC2, DNA, and nucleosome arrays. PHF1 phase separation promotes transcriptional repression as shown by luciferase reporter assays. Cellular observation (live imaging of condensates), biochemical reconstitution, luciferase reporter assay The Biochemical journal Medium 37888776
2018 PHF1 is required for accurate chromosome alignment and euploidy, and for asymmetric division during mouse meiotic oocyte maturation, as shown by morpholino-mediated knockdown of PHF1 in mouse oocytes. Morpholino knockdown, immunofluorescence, chromosome alignment analysis in mouse oocytes Cell cycle (Georgetown, Tex.) Low 30382790
2021 The crystal structure of PHF1 Tudor domain in complex with a peptidomimetic antagonist UNC6641 was determined; NMR and site-directed mutagenesis data defined the binding requirements of the Tudor domain for H3K36me3-mimicking ligands. X-ray crystallography, NMR, site-directed mutagenesis, TR-FRET binding assay Journal of medicinal chemistry Medium 33999620
2025 Using separation-of-function mutants in human pluripotent stem cells, PHF1-PRC2.1 was shown to deposit H3K27me3 at specific loci. PHF19 antagonizes MTF2-stimulated PRC2.1 activity; PHF1, MTF2, and PHF19 have distinct (not redundant) roles in epigenetic repression and cardiomyocyte differentiation. The PHF1-PRC2.1 subcomplex acts locus-specifically in opposition to PRC2.2. Separation-of-function mutant engineering in human pluripotent stem cells, ChIP-seq, differentiation assays bioRxiv (preprint)preprint Low bio_10.1101_2025.05.15.654236

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. Journal of neuroscience research 461 7534834
2008 Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation. The Journal of biological chemistry 223 18725412
2008 Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Molecular and cellular biology 222 18285464
2006 Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer research 183 16397222
2012 Molecular basis for H3K36me3 recognition by the Tudor domain of PHF1. Nature structural & molecular biology 152 23142980
2013 Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors--molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes, chromosomes & cancer 141 24285434
2012 Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. The American journal of pathology 104 22796436
2017 DNA binding by PHF1 prolongs PRC2 residence time on chromatin and thereby promotes H3K27 methylation. Nature structural & molecular biology 99 29058710
2008 A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell. Nucleic acids research 84 18385154
2012 Novel fusion of MYST/Esa1-associated factor 6 and PHF1 in endometrial stromal sarcoma. PloS one 82 22761769
2011 Structural impact of proline-directed pseudophosphorylation at AT8, AT100, and PHF1 epitopes on 441-residue tau. Journal of the American Chemical Society 81 21910444
2013 Binding of PHF1 Tudor to H3K36me3 enhances nucleosome accessibility. Nature communications 72 24352064
2018 PHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesis. Nucleic acids research 71 29846670
2013 PHF1 rearrangements in ossifying fibromyxoid tumors of soft parts: A fluorescence in situ hybridization study of 41 cases with emphasis on the malignant variant. The American journal of surgical pathology 71 23887158
2014 MEAF6/PHF1 is a recurrent gene fusion in endometrial stromal sarcoma. Cancer letters 66 24530230
2016 TFEB Overexpression in the P301S Model of Tauopathy Mitigates Increased PHF1 Levels and Lipofuscin Puncta and Rescues Memory Deficits. eNeuro 61 27257626
2016 Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 27927959
2019 Novel recurrent PHF1-TFE3 fusions in ossifying fibromyxoid tumors. Genes, chromosomes & cancer 52 30920708
2021 Phosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates. Frontiers in molecular neuroscience 47 34220449
2017 Generation and characterization of new monoclonal antibodies targeting the PHF1 and AT8 epitopes on human tau. Acta neuropathologica communications 45 28760159
2017 Fusion of the genes BRD8 and PHF1 in endometrial stromal sarcoma. Genes, chromosomes & cancer 44 28758277
2012 Tudor domains of the PRC2 components PHF1 and PHF19 selectively bind to histone H3K36me3. Biochemical and biophysical research communications 41 23228662
2006 Differential changes in phosphorylation of tau at PHF-1 and 12E8 epitopes during brain ischemia and reperfusion in gerbils. Neurochemical research 36 17191139
2003 GSK-3 dependent phosphoepitopes recognized by PHF-1 and AT-8 antibodies are present in different tau isoforms. Neurobiology of aging 36 14643380
2008 An endometrial stromal sarcoma cell line with the JAZF1/PHF1 chimera. Cancer genetics and cytogenetics 35 18722875
2018 Identification of an EPC2-PHF1 fusion transcript in low-grade endometrial stromal sarcoma. Oncotarget 34 29721194
2006 c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 16478768
2024 Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation. Proceedings of the National Academy of Sciences of the United States of America 31 38408247
2013 Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene. Human pathology 31 23806526
2013 JAZF1 rearrangement in a mesenchymal tumor of nonendometrial stromal origin: report of an unusual ossifying sarcoma of the heart demonstrating JAZF1/PHF1 fusion. The American journal of surgical pathology 28 23629446
2012 Polycomb group protein PHF1 regulates p53-dependent cell growth arrest and apoptosis. The Journal of biological chemistry 28 23150668
2020 A novel MBTD1-PHF1 gene fusion in endometrial stromal sarcoma: A case report and literature review. Genes, chromosomes & cancer 25 32237188
2020 Superficial malignant ossifying fibromyxoid tumors harboring the rare and recently described ZC3H7B-BCOR and PHF1-TFE3 fusions. Journal of cutaneous pathology 25 32352579
2017 PHF1 Tudor and N-terminal domains synergistically target partially unwrapped nucleosomes to increase DNA accessibility. Nucleic acids research 23 28082396
2016 Molecular Cytogenetic Analysis of JAZF1, PHF1, and YWHAE in Endometrial Stromal Tumors: Discovery of Genetic Complexity by Fluorescence in Situ Hybridization. The Journal of molecular diagnostics : JMD 23 27154512
2005 Caspase-3-mediated cleavage of PHF-1 tau during apoptosis irrespective of excitotoxicity and oxidative stress: an implication to Alzheimer's disease. Neurobiology of disease 23 15755671
2019 Fusion of the Genes PHF1 and TFE3 in Malignant Chondroid Syringoma. Cancer genomics & proteomics 22 31467228
2016 The Tyr216 phosphorylated form of GSK3β contributes to tau phosphorylation at PHF-1 epitope in response to Aβ in the nucleus of SH-SY5Y cells. Life sciences 21 27343974
2000 The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid. Neuroscience letters 19 10713393
2022 Down-regulated m6A reader FTO destabilizes PHF1 that triggers enhanced stemness capacity and tumor progression in lung adenocarcinoma. Cell death discovery 18 35945194
2021 Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1). Journal of medicinal chemistry 17 33999620
2023 Expanding the molecular signatures of malignant ossifying fibromyxoid tumours with two novel gene fusions: PHF1::FOXR1 and PHF1::FOXR2. Histopathology 11 36648026
2021 A PHF1-TFE3 fusion atypical ossifying fibromyxoid tumor with prominent collagenous rosettes: Case report with a brief review. Experimental and molecular pathology 8 34560087
2018 PHF1 is required for chromosome alignment and asymmetric division during mouse meiotic oocyte maturation. Cell cycle (Georgetown, Tex.) 8 30382790
2023 PHF1 compartmentalizes PRC2 via phase separation. The Biochemical journal 7 37888776
2021 Ossifying low grade endometrial stromal sarcoma with PHF1-BRD8 fusion. Cancer genetics 4 33975123
2025 PHF1::TFE3-positive fibromyxoid sarcoma? Report of 2 cases and review of 13 cases of PHF1::TFE3-positive ossifying fibromyxoid tumor in the literature. American journal of clinical pathology 3 39250713
2021 Low-grade Endometrial Stromal Sarcoma With Sex Cord-like Differentiation and PHF1-JAZF1 Fusion With Deletions: A Diagnostic Pitfall of JAZF1 FISH. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 3 34074959
2021 Round cell tumor with a myxoid matrix harboring a PHF1-TFE3 fusion: Myoepithelial neoplasm or ossifying fibromyxoid tumor? Pathology, research and practice 3 34391181
2022 An amino-terminal fragment of apolipoprotein E4 leads to behavioral deficits, increased PHF-1 immunoreactivity, and mortality in zebrafish. PloS one 2 36520946
2026 Discovery of Small-Molecule Antagonists of PHF1 and 19 Demonstrates the Ligandability of PRC2 Accessory Proteins. ACS bio & med chem Au 0 42006253
2025 Effect of PHF-1 hyperphosphorylation on the seeding activity of C-terminal Tau fragments. Scientific reports 0 40121258
2025 Ossification-deficient atypical ossifying fibromyxoid tumor of submandibular gland with PHF1::EP400 fusion: diagnostic challenges. Oral and maxillofacial surgery 0 41068353
2024 Characterization of Posttranslationally Modified PHF-1 Tau Peptides Using Gaussian Accelerated Molecular Dynamics Simulation. Methods in molecular biology (Clifton, N.J.) 0 38512658
2024 Aggressive Malignant Ossifying Fibromyxoid Tumor With a Rare PHF1::FOXR2 Fusion: A Case Report and Literature Review. International journal of surgical pathology 0 39552609

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