Affinage

PHF20

PHD finger protein 20 · UniProt Q9BVI0

Length
1012 aa
Mass
115.4 kDa
Annotated
2026-06-10
24 papers in source corpus 16 papers cited in narrative 16 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

PHF20 is a multidomain epigenetic reader and core subunit of the MOF (MYST1)/NSL lysine acetyltransferase complex that couples recognition of methylated lysines on histones and non-histone proteins to transcriptional activation and protein stabilization (PMID:22864287, PMID:22072714). Its tandem Tudor domains, particularly Tudor domain 2, directly engage dimethyl-lysine marks: a homodimeric form binds p53 dimethylated at Lys370 and Lys382 with multivalent affinity, and this binding blocks Mdm2-mediated ubiquitylation to stabilize and activate p53 (PMID:22864287, PMID:22449972). Its PHD finger selectively recognizes H3K4me2, an interaction required for MOF-NSL-dependent histone acetylation, chromatin recruitment, and target-gene activation (PMID:27760318); PHF20 also reads H3K36me2 at enhancers to sustain chromatin accessibility and autophagy gene expression under glucose starvation (PMID:35821310). Through these readout activities PHF20 occupies and activates a range of target loci, driving stem-cell genes OCT4/SOX2 via PARP1 association (PMID:29452418), the WISP1/β-Catenin axis via WDR5 (PMID:33117706), and osteogenic programs through Runx2 and a METTL14–HOXA13 m6A cascade (PMID:28808306, PMID:39757292). Beyond chromatin, PHF20 sustains NF-κB activity by binding methylated p65 and excluding PP2A to maintain p65 phosphorylation (PMID:23797602), and promotes ubiquitin-mediated degradation of GAS7 to limit nuclear F-actin assembly and DNA damage (PMID:42215448). PHF20 abundance and activity are tightly controlled: Akt phosphorylates Ser291 to drive nuclear-to-cytoplasmic shuttling and attenuate p53 induction (PMID:22334668, PMID:22975685), Jmjd3 recruits the E3 ligase Trim26 for its degradation (PMID:23452852), and ALKBH5 destabilizes PHF20 mRNA via m6A removal (PMID:35979628). Homozygous PHF20 deletion in humans causes a neurodevelopmental syndrome accompanied by loss of H4K16 acetylation at neuronal-development genes, establishing PHF20 as essential for the developmental output of MOF-NSL function (PMID:41438488).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 High

    Established that PHF20 is a methyl-lysine reader that stabilizes p53, answering how a dimethyl mark on p53 is converted into protection from degradation.

    Evidence Biochemical/biophysical binding assays of homodimeric Tudor domain 2 with p53 K370me2/K382me2, plus cellular stabilization and ubiquitylation assays; corroborated by crystal structures of both N-terminal Tudor domains showing dimethyl-lysine preference

    PMID:22449972 PMID:22864287

    Open questions at the time
    • Identity of the methyltransferase generating these p53 marks in vivo not resolved by these studies
    • Stoichiometry and contribution within the full MOF-NSL complex not addressed
  2. 2012 High

    Defined Akt-mediated Ser291 phosphorylation as a switch that exports PHF20 to the cytoplasm and dampens its p53/p21 response, linking growth signaling to the PHF20-p53 axis.

    Evidence In vitro kinase reconstitution, in vivo phosphorylation, subcellular fractionation, and p53/p21 transcription reporter assays including UV-damage context

    PMID:22334668 PMID:22975685

    Open questions at the time
    • Whether cytoplasmic PHF20 has a distinct function not addressed
    • Upstream signals coupling Akt to PHF20 in specific stress contexts unclear
  3. 2011 Medium

    Placed PHF20 within the MOF acetyltransferase complex but as a downstream transcriptional effector rather than a determinant of global H4K16 acetylation, refining its role in the complex.

    Evidence PHF20-knockout mice with H4K16ac ChIP and MOF target-gene expression analysis

    PMID:22072714

    Open questions at the time
    • Molecular basis for transcriptional effect independent of H4K16ac not defined
    • Tissue-specific contributions to skeletal/hematopoietic phenotypes not dissected
  4. 2013 High

    Revealed two distinct regulatory layers: Jmjd3/Trim26 degrades PHF20 to restrain reprogramming, and PHF20 sustains NF-κB by blocking PP2A from methylated p65.

    Evidence Reciprocal Co-IP, ubiquitination and E3 ligase recruitment assays with PHF20-KO MEFs and iPSC reprogramming (Jmjd3); Co-IP, p65 phosphorylation, EMSA/reporter and TNF-induced NF-κB assays (p65)

    PMID:23452852 PMID:23797602

    Open questions at the time
    • Methyltransferase generating the p65 methyl mark read by PHF20 not identified
    • Demethylase-independent Jmjd3 function not generalized beyond reprogramming
  5. 2016 High

    Identified the PHD finger as an H3K4me2 reader required for MOF-NSL acetylation and chromatin recruitment, defining how PHF20 couples a histone mark to transcriptional output.

    Evidence Biochemical binding assays, structural analysis, ChIP, and transcriptional activation assays with PHD finger mutants

    PMID:27760318

    Open questions at the time
    • Interplay between PHD H3K4me2 reading and Tudor methyl-protein reading not integrated
    • Genome-wide target set of PHD-dependent recruitment incompletely mapped
  6. 2017 Medium

    Connected PHF20 to context-specific gene programs, showing it activates OCT4/SOX2 stemness genes and Runx2-driven osteogenic genes through promoter occupancy and H3K4 methylation.

    Evidence Co-IP (PARP1, Runx2), ChIP for promoter occupancy and H3K4me3, promoter reporters, and CRISPR/knockdown with phenotypic rescue

    PMID:28808306 PMID:29452418

    Open questions at the time
    • Direct causal link between PHF20 catalytic-complex activity and the observed H3K4me3 changes not established
    • Single-lab cancer/differentiation models limit generality
  7. 2020 Medium

    Extended PHF20 target programs to the WISP1/BGN/β-Catenin axis via WDR5 partnership in glioblastoma.

    Evidence Co-IP (PHF20-WDR5), ChIP at WISP1 promoter, PHF20 knockout with pathway analysis

    PMID:33117706

    Open questions at the time
    • Whether WDR5 partnership is part of MOF-NSL or a separate assembly unclear
    • Single tumor-context study without reciprocal validation
  8. 2022 Medium

    Showed PHF20 reads H3K36me2 at enhancers to maintain chromatin accessibility and autophagy gene expression, and that ALKBH5 controls PHF20 abundance post-transcriptionally via m6A.

    Evidence ATAC-seq, ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq with KO/KD and autophagy flux assays; MeRIP-seq, m6A mapping and mRNA stability assays for ALKBH5 regulation

    PMID:35821310 PMID:35979628

    Open questions at the time
    • Domain responsible for H3K36me2 reading versus PHD/Tudor not delineated
    • Mechanism linking enhancer accessibility to H3K4me1/2 increase not resolved
  9. 2025 Medium

    Linked PHF20 to a human neurodevelopmental syndrome and to an osteogenic m6A cascade, establishing developmental requirements for PHF20-dependent H4K16 acetylation.

    Evidence Patient-derived cells with Western blot of NSL subunits, RNA-seq and H4K16ac epigenomics, microarray/exome sequencing (syndrome); ChIP at METTL14 promoter, RIP for IGF2BP3/m6A on HOXA13, mRNA stability assays (osteogenesis)

    PMID:39757292 PMID:41438488

    Open questions at the time
    • Causality of specific mutations versus deletion in patients not fully dissected
    • Whether neuronal H4K16ac loss is direct or secondary to NSL dysregulation unclear
  10. 2026 Medium

    Defined a new non-chromatin role: PHF20 drives ubiquitin-mediated GAS7 degradation to limit nuclear F-actin and DNA damage, implicating it in DNA damage repair regulation.

    Evidence Co-IP, ubiquitination assays, KD/KO with GAS7 stability, nuclear F-actin imaging, γH2AX DNA damage assays, and in vivo xenograft

    PMID:42215448

    Open questions at the time
    • Whether PHF20 acts as or recruits an E3 ligase for GAS7 not established
    • Single study without reciprocal validation of the GAS7 mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PHF20's multiple reader modules (Tudor domains, PHD finger) are coordinated on chromatin versus on non-histone substrates, and how this integrates the diverse target programs into a unified function, remains unresolved.
  • No integrated structural model of full-length PHF20 within MOF-NSL
  • Rules governing choice between p53/p65 reading and histone reading unknown
  • Relative contribution of catalytic-complex versus reader-only functions in disease unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
GAS7KDM6BPARP1RELARUNX2TP53WDR5
Complex memberships
MOF-NSL acetyltransferase complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 The Tudor domain 2 of PHF20 directly binds p53 dimethylated at Lys370 or Lys382; a homodimeric form of this Tudor domain associates with both dimethylated sites on p53 with enhanced (multivalent) affinity. PHF20 binding to methylated p53 diminishes Mdm2-mediated p53 ubiquitylation and degradation, thereby stabilizing and activating p53. Biochemical and biophysical binding assays (multivalent Tudor domain interaction), cellular stabilization assays, p53 ubiquitylation assays Nature structural & molecular biology High 22864287
2012 Crystal structures of both N-terminal Tudor domains of PHF20 reveal novel structural variations; Tudor domain 2 exhibits preference for dimethylated histone substrates (confirmed biochemically). X-ray crystallography; biochemical binding assays confirming dimethyl-lysine preference FEBS letters High 22449972
2013 Jmjd3 targets PHF20 for ubiquitination and proteasomal degradation via recruitment of the E3 ubiquitin ligase Trim26, representing a histone demethylase-independent mechanism by which Jmjd3 inhibits somatic cell reprogramming. PHF20 is required for full reprogramming to iPSCs, as PHF20-deficient MEFs cannot be converted to fully reprogrammed iPSCs even with knockdown of Jmjd3, Ink4a, or p21. Co-immunoprecipitation, ubiquitination assays, Jmjd3/Trim26 E3 ligase recruitment assay, PHF20-knockout MEFs, iPSC reprogramming assay Cell High 23452852
2013 PHF20 maintains NF-κB in an active state by binding methylated lysine residues on p65, which prevents PP2A from associating with p65 and thereby sustains p65 phosphorylation and NF-κB DNA-binding activity. Co-immunoprecipitation, p65 phosphorylation assays, DNA-binding (EMSA/reporter) assays, TNF-induced NF-κB activation assays in PHF20-overexpressing cells Nature communications High 23797602
2012 Akt/PKB directly phosphorylates PHF20 at Ser291 in vitro and in vivo; this phosphorylation causes translocation of PHF20 from the nucleus to the cytoplasm and attenuates its ability to induce p53 transcription. In vitro kinase assay, in vivo phosphorylation, subcellular fractionation/localization, p53 transcription reporter assays The Journal of biological chemistry High 22334668
2012 PKB/Akt-mediated PHF20 phosphorylation at Ser291 inhibits p53 induction following UV-induced DNA damage, reducing p21 transcriptional activity. In vitro and in vivo phosphorylation assays, UV-damage experiments, p21 transcription reporter assay Cellular signalling Medium 22975685
2016 The PHD finger of PHF20 directly recognizes H3K4me2 (dimethylated lysine 4 on histone H3); this interaction is required for histone acetylation by the MOF-NSL complex, accumulation of PHF20 at target gene loci, and transcriptional activation. Structural analysis explains selectivity for H3K4me2 over other methylation states. Biochemical binding assays, structural analysis (crystallography/NMR referenced), chromatin immunoprecipitation, transcriptional activation assays with PHD finger mutants Cell reports High 27760318
2011 PHF20 is a component of the MOF histone acetyltransferase complex but is not required for maintaining global or locus-specific H4K16 acetylation levels; instead, PHF20 acts downstream in transcriptional regulation of MOF target genes. PHF20-knockout mice die shortly after birth with skeletal and hematopoietic phenotypes. PHF20-knockout mouse generation; H4K16 acetylation ChIP; gene expression analysis of MOF target genes The Journal of biological chemistry Medium 22072714
2018 PHF20 interacts with PARP1 and directly binds the promoter regions of OCT4 and SOX2, modulating the H3K4me3 histone mark at these loci to sustain stem cell-like properties in neuroblastoma cells. Co-immunoprecipitation (PHF20-PARP1 interaction), ChIP (PHF20 promoter occupancy, H3K4me3), CRISPR/Cas9 PHF20 knockout with phenotypic rescue by OCT4/SOX2 overexpression Journal of molecular cell biology Medium 29452418
2020 PHF20 interacts with WDR5 and directly binds to the promoter region of WISP1 to drive its expression; WISP1 and BGN then act together to regulate β-Catenin degradation in glioblastoma cells. Co-immunoprecipitation (PHF20-WDR5), ChIP (PHF20 at WISP1 promoter), PHF20 knockout with WISP1/BGN/β-Catenin pathway analysis Frontiers in oncology Medium 33117706
2022 PHF20 recognizes H3K36me2 at enhancer regions, and this binding is associated with increased H3K4me1/2 levels at those enhancers; PHF20 deficiency impairs chromatin accessibility at enhancers and reduces autophagy gene expression under glucose starvation. ATAC-seq (chromatin accessibility), ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq, Phf20 knockdown/KO with autophagic flux assays Nucleic acids research Medium 35821310
2022 ALKBH5-mediated demethylation of m6A on PHF20 mRNA 3'UTR reduces PHF20 mRNA stability; thus ALKBH5 suppresses PHF20 protein expression post-transcriptionally via m6A modification. MeRIP-seq and RNA-seq joint analysis, m6A site mapping, mRNA stability assays, ALKBH5 knockdown/overexpression Clinical and translational medicine Medium 35979628
2017 PHF20 directly associates with Runx2 at osteogenic gene promoters and increases H3K4me3 enrichment at the Runx2 promoter, thereby activating Runx2 expression and downstream osteoblast differentiation genes. Co-immunoprecipitation (PHF20-Runx2), ChIP (H3K4me3 at Runx2 promoter), promoter reporter assays, PHF20 overexpression/knockdown with differentiation markers Scientific reports Medium 28808306
2025 PHF20 elevates METTL14 expression by enhancing H3K4me3 enrichment on the METTL14 promoter; METTL14 in turn promotes m6A methylation of HOXA13 mRNA, which is recognized by IGF2BP3 to stabilize HOXA13 mRNA, facilitating osteogenic differentiation of mesenchymal stem cells. ChIP (H3K4me3 at METTL14 promoter), RIP (IGF2BP3/m6A enrichment on HOXA13 mRNA), mRNA stability assays (actinomycin D), PHF20 knockdown with differentiation readouts Functional & integrative genomics Medium 39757292
2026 PHF20 interacts with GAS7 and promotes its ubiquitin-mediated proteasomal degradation; loss of PHF20 stabilizes GAS7, which is associated with enhanced nuclear F-actin assembly and increased DNA damage accumulation, implicating PHF20 in DNA damage repair regulation. Co-immunoprecipitation, ubiquitination assays, PHF20 knockdown/KO with GAS7 stability, nuclear F-actin imaging, DNA damage assays (γH2AX), in vivo xenograft Cell death & disease Medium 42215448
2025 Homozygous deletion of PHF20 in humans leads to a neurodevelopmental syndrome; loss of PHF20 causes reduction of H4K16 acetylation at genes involved in neuronal development and cell projection, without altering levels of other NSL complex subunits. Western blot (PHF20 and NSL subunit levels in patient cells), transcriptomic analysis (RNA-seq), epigenomic analysis (H4K16ac ChIP or CUT&RUN), chromosomal microarray and exome sequencing Human mutation Medium 41438488

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell 129 23452852
2012 PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53. Nature structural & molecular biology 83 22864287
2013 PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65. Nature communications 50 23797602
2022 N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation. Clinical and translational medicine 45 35979628
2016 PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation. Cell reports 42 27760318
2011 Loss of the methyl lysine effector protein PHF20 impacts the expression of genes regulated by the lysine acetyltransferase MOF. The Journal of biological chemistry 31 22072714
2012 PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage. Cellular signalling 28 22975685
2018 PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4. Journal of molecular cell biology 27 29452418
2012 Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53. The Journal of biological chemistry 24 22334668
2012 Crystal structures of the Tudor domains of human PHF20 reveal novel structural variations on the Royal Family of proteins. FEBS letters 20 22449972
2017 PHF20 positively regulates osteoblast differentiation via increasing the expression and activation of Runx2 with enrichment of H3K4me3. Scientific reports 18 28808306
2022 PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation. Nucleic acids research 16 35821310
2020 PHF20 Promotes Glioblastoma Cell Malignancies Through a WISP1/BGN-Dependent Pathway. Frontiers in oncology 14 33117706
2021 PHF20 inhibition promotes apoptosis and cisplatin chemosensitivity via the OCT4‑p‑STAT3‑MCL1 signaling pathway in hypopharyngeal squamous cell carcinoma. International journal of oncology 12 33982773
2021 circCUX1 promotes neuroblastoma progression and glycolysis by regulating the miR-338-3p/PHF20 axis. General physiology and biophysics 8 33655888
2019 Molecular genetic characterization reveals linear tumor evolution in a pulmonary sarcomatoid carcinomas patient with a novel PHF20-NTRK1 fusion: a case report. BMC cancer 7 31208361
2023 Long non-coding RNA PCAT5 regulates the progression of Esophageal Squamous Cell Carcinoma via miR-4295/PHF20. Heliyon 5 38046167
2025 Epigenetic modification mediated by PHF20/METTL14/HOXA13 signaling axis modulates osteogenic differentiation of mesenchymal stem cells. Functional & integrative genomics 3 39757292
2024 Enhancement of renal fibrosis in PHF20 transgenic mice. Toxicological research 2 39802116
2023 Corrigendum: PHF20 promotes glioblastoma cell malignancies through a WISP1/BGN-dependent pathway. Frontiers in oncology 2 37035210
2015 [The expression and clinical significance of Bax and PHF20 in laryngeal squamous cell carcinoma]. Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery 2 26999840
2026 PHF20 stabilizes the GAS7-F-actin axis to drive DNA damage repair and chemoresistance in cutaneous squamous cell carcinoma. Cell death & disease 0 42215448
2025 Homozygous Deletion of the Epigenetic Regulator PHF20 in Individuals With Neurodevelopmental Disorder. Human mutation 0 41438488
2018 Structure-based analysis of curcumin and conventionaldrugs targeting tumor-inducing protein PHF20. Bioinformation 0 31223206

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