Affinage

YAF2

YY1-associated factor 2 · UniProt Q8IY57

Length
180 aa
Mass
19.9 kDa
Annotated
2026-06-11
22 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

YAF2 is a substoichiometric component of variant (noncanonical) Polycomb Repressive Complex 1 that couples Polycomb recruitment to maintenance of the repressive H2AK119ub1 mark and thereby controls developmental gene silencing (PMID:32203418, PMID:29959227). It assembles into vPRC1 through a region spanning residues 102–150 and partners with the catalytic E3 ligase Ring1B (and Ring1A) to drive H2A monoubiquitination (PMID:29959227, PMID:14557078). As a reader-writer module, YAF2 binds H2AK119ub1 and directs the YAF2-PRC1 complex to ubiquitinate H2A on neighboring nucleosomes, a positive-feedback mechanism that propagates the mark through cell division and is enhanced by histone H1-compacted chromatin (PMID:32203418). Sequence-specific targeting is achieved by bridging the transcription factor YY1 to PRC1: YAF2 binds the YY1 REPO domain and YY1 DNA binding is a prerequisite for Polycomb assembly at target loci (PMID:24285299, PMID:19960508). YAF2 phosphorylation at Ser166 is required for efficient Ring1B-mediated H2A ubiquitination and target-gene repression, and loss of Yaf2 in embryonic stem cells compromises proliferation, perturbs differentiation, and de-represses lineage genes (PMID:29959227, PMID:37935677). YAF2 and its paralog RYBP regulate largely distinct Polycomb target sets and have opposing effects on neural differentiation (PMID:24285299, PMID:37935677). Beyond chromatin, YAF2 binds and differentially modulates MycN (activating) versus Myc (inhibitory) transcriptional activity (PMID:11593398, PMID:12706874), stabilizes PDCD5 to promote TP53-dependent apoptotic signaling under genotoxic stress (PMID:25603536), and, when phosphorylated, stabilizes FANK1 to suppress apoptosis (PMID:33784512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 Medium

    Established YAF2 as a Myc-family transcriptional cofactor by showing it binds the central region of nuclear MycN and enhances E-box-driven transactivation, framing an early non-chromatin function.

    Evidence Yeast two-hybrid, in vitro/in vivo binding, E-box reporter and MycN deletion mutagenesis

    PMID:11593398

    Open questions at the time
    • Mechanism by which YAF2 boosts MycN activity unresolved
    • No genome-wide MycN target validation
  2. 2002 Medium

    Showed YAF2 interacts with hGABPβ and YY1 and positively regulates transcription, contrasting it functionally with RYBP and hinting at distinct paralog roles.

    Evidence Yeast two/three-hybrid, in vitro/in vivo binding, transcriptional reporter assays

    PMID:11953439

    Open questions at the time
    • Direct chromatin occupancy not demonstrated
    • Relationship of GABP activation to Polycomb function unclear
  3. 2003 Medium

    Connected YAF2 to the Polycomb machinery by demonstrating its interaction with Ring1B/Ring1A, placing it within mammalian PcG complexes.

    Evidence Co-IP and colocalization in tissue culture, identification of splice isoforms

    PMID:14557078

    Open questions at the time
    • Catalytic consequence of YAF2-Ring1B interaction not yet shown
    • Target genes undefined
  4. 2003 Medium

    Revealed opposing regulation within the Myc family by showing YAF2 inhibits Myc-mediated transactivation and transformation, unlike its activating effect on MycN.

    Evidence In vitro/in vivo binding, reporter and transformation assays

    PMID:12706874

    Open questions at the time
    • Structural basis for opposite Myc vs MycN effects unknown
    • In vivo relevance to tumorigenesis untested
  5. 2006 Medium

    Demonstrated an essential survival function for YAF2 in vivo, as depletion in zebrafish triggers caspase 8-mediated apoptosis rescuable by human YAF2, establishing an anti-apoptotic role.

    Evidence Morpholino knockdown, caspase-inhibitor and mRNA rescue, apoptosis assays

    PMID:16891308

    Open questions at the time
    • Molecular link between YAF2 and caspase 8 not defined
    • Relationship to Polycomb activity unaddressed
  6. 2010 Medium

    Mapped sequence-specific Polycomb recruitment to the YY1 REPO domain–YAF2 interaction, showing YAF2 can recruit PcG proteins and repress transcription when tethered to DNA.

    Evidence Co-IP, REPO deletion mutagenesis, heterologous DNA-binding domain fusion repression, Drosophila dRYBP genetics

    PMID:19960508

    Open questions at the time
    • Endogenous YY1-YAF2 target loci not enumerated
    • Stoichiometry of bridging complex unknown
  7. 2013 High

    Defined YAF2 as the obligate bridge between YY1 DNA binding and PRC1 recruitment and distinguished its target gene set from RYBP, clarifying paralog-specific Polycomb function.

    Evidence Reciprocal Co-IP, ChIP, YY1 knockdown/rescue, cross-species dRYBP complementation

    PMID:24285299

    Open questions at the time
    • Genome-wide map of YY1-dependent vs independent YAF2 targets incomplete
    • How distinct YAF2 vs RYBP targeting is achieved unknown
  8. 2015 Medium

    Identified a TP53-axis function: YAF2 binds and stabilizes PDCD5 against proteasomal degradation to promote TP53 activation during genotoxic stress.

    Evidence Yeast two-hybrid, Co-IP, siRNA, ubiquitination assays, etoposide stress, PDCD5 mutant rescue

    PMID:25603536

    Open questions at the time
    • How YAF2 protects PDCD5 from ubiquitination mechanistically unclear
    • Reconciliation with anti-apoptotic role not addressed
  9. 2018 High

    Provided the integrated chromatin mechanism: YAF2 assembles into noncanonical PRC1 via residues 102–150 and its Ser166 phosphorylation is required for Ring1B-driven H2A ubiquitination, with Yaf2 loss in mESCs causing differentiation defects and gene de-repression.

    Evidence Co-IP, deletion and S166A mutagenesis, ChIP-seq, in vitro H2A ubiquitination, mESC knockout

    PMID:29959227

    Open questions at the time
    • Kinase responsible for Ser166 phosphorylation unidentified
    • Structural detail of the 102–150 assembly region absent
  10. 2020 High

    Established YAF2 as a reader-writer that propagates H2AK119ub1 through a positive-feedback loop, explaining heritable maintenance of the mark across cell division.

    Evidence Biochemical binding assays, chromatin fractionation, H1-compaction and cell division readouts, RYBP/YAF2-PRC1 disruption

    PMID:32203418

    Open questions at the time
    • Quantitative contribution of YAF2 vs RYBP to propagation in vivo unclear
    • How H1 compaction enhances distal spreading mechanistically undefined
  11. 2021 Medium

    Extended YAF2's adaptor role to chromatin-modifying deacetylation by showing it bridges YY1 and SIRT6 at 1:1:1 stoichiometry to accelerate H3K9 deacetylation and mitochondrial gene downregulation.

    Evidence Pulldown, cross-linking molar ratio, ChIP-qPCR, SIRT6 inhibition (tunicate model)

    PMID:33875574

    Open questions at the time
    • Relevance to mammalian aging untested
    • Independence from PRC1 function unclear
  12. 2021 Medium

    Provided a phosphorylation-dependent anti-apoptotic mechanism: phospho-Ser167 YAF2 stabilizes polyubiquitinated FANK1 by binding its FN3 domain, suppressing tumor cell apoptosis.

    Evidence Co-IP, siRNA, proteasome inhibition, FN3/N-terminus domain mapping, phosphorylation and apoptosis assays

    PMID:33784512

    Open questions at the time
    • Kinase and signaling input for Ser167 unknown
    • Relationship between Ser166 (chromatin) and Ser167 (FANK1) phosphorylation events unresolved
  13. 2023 High

    Resolved divergent paralog function in differentiation: Yaf2 loss redistributes RYBP and H2AK119ub onto co-targeted genes and promotes neural differentiation, opposite to Rybp loss, showing YAF2 restrains ectopic lineage gene activation.

    Evidence Rybp and Yaf2 KO mESCs, RYBP and H2AK119ub ChIP-seq, transcriptional profiling, neural differentiation assays

    PMID:37935677

    Open questions at the time
    • Mechanism driving RYBP redistribution upon Yaf2 loss undefined
    • Direct interplay with Wnt signaling not dissected for YAF2

Open questions

Synthesis pass · forward-looking unresolved questions
  • How YAF2's chromatin (vPRC1/H2AK119ub1) functions are mechanistically coordinated with its apoptosis-regulating roles (PDCD5/TP53 activation versus caspase 8 and FANK1-dependent survival), and which kinases control its functionally critical Ser166/Ser167 phosphorylation, remains unresolved.
  • Upstream kinase for Ser166/167 unidentified
  • No unified model reconciling pro- and anti-apoptotic activities
  • No structural model of YAF2 in vPRC1 or its phospho-regulated states

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140110 transcription regulator activity 3 GO:0140313 molecular sequestering activity 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3
Complex memberships
variant Polycomb Repressive Complex 1 (vPRC1)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 YAF2 specifically binds H2AK119ub1 and recruits the YAF2-PRC1 complex to catalyse ubiquitination of H2A on neighbouring nucleosomes through a positive-feedback model, propagating H2AK119ub1 during cell division; histone H1-compacted chromatin enhances distal propagation of this mark. Biochemical binding assays, chromatin fractionation, cell division assays; disruption of RYBP/YAF2-PRC1 activity or H1-dependent compaction caused significant loss of H2AK119ub1 maintenance Nature cell biology High 32203418
2013 YAF2 bridges the interaction between YY1 and the PRC1 complex; YAF2 is responsible for PcG recruitment to DNA, which is mediated by YY1 DNA binding. Knock-down of YY1 abrogated PcG recruitment even when exogenous YAF2 was present, showing YY1 DNA binding is a prerequisite for Polycomb assembly. YAF2 and RYBP regulate largely distinct sets of Polycomb target genes. Co-IP, ChIP assays in HeLa cells, YY1 knock-down, rescue with exogenous YAF2, dRYBP mutant fly complementation with mouse YAF2 Nucleic acids research High 24285299
2002 YAF2 interacts with hGABPβ and YY1 both in vitro and in vivo, and positively regulates transcriptional activity of hGABP, functionally distinct from YEAF1/RYBP which negatively regulates hGABP activity. Yeast two-hybrid screening, yeast three-hybrid assay, in vitro and in vivo binding assays, transcriptional reporter assays The Journal of biological chemistry Medium 11953439
2010 The YY1 REPO domain (25 amino acids) interacts with YAF2 and recruits YAF2 to DNA; deletion of the REPO domain abolishes this interaction. YAF2, when fused to a heterologous DNA-binding domain, can recruit PcG proteins to DNA and mediate transcriptional repression. Mutation of the Drosophila YAF2 homolog (dRYBP) reduces PcG recruitment to DNA. Co-IP, transcriptional repression assays with heterologous DNA-binding domain fusion, deletion mutagenesis of YY1 REPO domain, Drosophila dRYBP mutant analysis Journal of cellular biochemistry Medium 19960508
2006 Zebrafish Yaf2 is required for cell survival during embryogenesis; depletion activates widespread caspase 8-mediated apoptosis and causes developmental arrest. Human YAF2 mRNA rescues this phenotype, and YAF2 inhibits caspase 8-mediated apoptosis in cultured cells. Morpholino knockdown in zebrafish, caspase inhibitor rescue (pan-caspase and caspase 8-specific), human YAF2 mRNA rescue, apoptosis assays in cultured cells The Journal of biological chemistry Medium 16891308
2001 YAF2 binds to the central region of MycN in vitro and in vivo, localizes to the nucleus, and enhances MycN-mediated transactivation from an E-box promoter; deletion of the YAF2-binding region in MycN abrogates this enhancement. Yeast two-hybrid, in vitro binding assay, in vivo co-immunoprecipitation, nuclear localization by cell imaging, E-box reporter transactivation assay, deletion mutagenesis of MycN Oncogene Medium 11593398
2003 YAF2 binds to the Myc protein in vivo and in vitro, but in contrast to its activating effect on MycN, YAF2 inhibits Myc-mediated transactivation and transformation. In vitro binding, in vivo co-immunoprecipitation, transcriptional reporter assays, transformation assays Cancer letters Medium 12706874
2003 Mouse YAF2 interacts with Ring1B (and Ring1A), a constituent of mammalian PcG complexes; biochemical and colocalization evidence in tissue culture cells supports YAF2 involvement in PcG complexes together with Ring1B/Ring1A. Co-immunoprecipitation, colocalization studies in tissue culture cells, identification of two YAF2 isoforms by alternative splicing Gene Medium 14557078
2015 YAF2 binds PDCD5 and stabilizes it by inhibiting ubiquitin-dependent proteasomal degradation, thereby promoting TP53 activation during genotoxic stress. YAF2 knockdown reduces PDCD5 protein (not mRNA) levels. YAF2 promotion of TP53 activation is abolished by PDCD5 deletion and restored by wild-type PDCD5 but not by YAF2-interaction-defective PDCD5 mutants. Yeast two-hybrid screen, co-IP, siRNA knockdown, ubiquitination assays, genotoxic stress assays (etoposide), apoptosis rescue with PDCD5 mutants Biochimica et biophysica acta Medium 25603536
2018 YAF2 assembles into a noncanonical PRC1 complex via a region encompassing amino acid residues 102–150. Serine 166 is a YAF2 phosphorylation site; S166A mutation compromises Ring1B-mediated H2A monoubiquitination and repression of target genes. Yaf2 deletion in mESCs causes compromised proliferation, abnormal differentiation, and de-repression of ectoderm-associated genes. Yeast two-hybrid, co-IP, deletion mutagenesis (residues 102–150), phosphorylation site mutagenesis (S166A), genome-wide profiling (ChIP-seq), H2A ubiquitination assays, mESC knockout The Journal of biological chemistry High 29959227
2021 YAF2 mediates interaction between YY1 and SIRT6; pulldown assays show YAF2 associates with both YY1 and SIRT6 at a 1:1:1 molar ratio. YAF2 and YY1 accelerate SIRT6-induced H3K9 deacetylation at the TFAM gene upstream region, contributing to age-related mitochondrial downregulation. Pulldown assays, protein cross-linking (molar ratio determination), ChIP-qPCR for H3K9 deacetylation, mRNA transfection experiments, SIRT6 inhibitor treatment Molecular and cellular biology Medium 33875574
2021 Phosphorylated YAF2 (at Serine 167) inhibits proteasomal degradation of polyubiquitinated FANK1 by binding to the FN3 domain of FANK1 via the amino-terminal region of YAF2, increasing FANK1 stability and thereby inhibiting tumor cell apoptosis in a FANK1-dependent manner. Co-IP, siRNA knockdown, proteasome inhibitor assays, domain mapping (FN3 domain of FANK1 binds N-terminus of YAF2), phosphorylation analysis, apoptosis assays Biochemical and biophysical research communications Medium 33784512
2023 RYBP and YAF2 have distinct regulatory functions in neural differentiation: Rybp knockout impairs neural differentiation by activating Wnt signaling; Yaf2 knockout promotes neural differentiation and leads to redistribution of RYBP binding with increased RYBP and H2AK119ub enrichment on RYBP-YAF2 co-targeted genes, preventing ectopic derepression of non-neuroectoderm genes. Knockout mESC lines (Rybp KO, Yaf2 KO), ChIP-seq for RYBP and H2AK119ub, genome-wide transcriptional profiling, neural differentiation assays Nature communications High 37935677

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 RYBP/YAF2-PRC1 complexes and histone H1-dependent chromatin compaction mediate propagation of H2AK119ub1 during cell division. Nature cell biology 93 32203418
2022 Human Amniotic Fluid Mesenchymal Stem Cell-Derived Exosomes Inhibit Apoptosis in Ovarian Granulosa Cell via miR-369-3p/YAF2/PDCD5/p53 Pathway. Oxidative medicine and cellular longevity 54 35936223
2013 YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment. Nucleic acids research 54 24285299
2002 YEAF1/RYBP and YAF-2 are functionally distinct members of a cofactor family for the YY1 and E4TF1/hGABP transcription factors. The Journal of biological chemistry 50 11953439
2010 PcG recruitment by the YY1 REPO domain can be mediated by Yaf2. Journal of cellular biochemistry 44 19960508
2020 TV-circRGPD6 Nanoparticle Suppresses Breast Cancer Stem Cell-Mediated Metastasis via the miR-26b/YAF2 Axis. Molecular therapy : the journal of the American Society of Gene Therapy 31 32950105
2006 Yaf2 inhibits caspase 8-mediated apoptosis and regulates cell survival during zebrafish embryogenesis. The Journal of biological chemistry 28 16891308
2019 miR-34b inhibits the migration/invasion and promotes apoptosis of non-small-cell lung cancer cells by YAF2. European review for medical and pharmacological sciences 19 30915747
2021 YAF2-Mediated YY1-Sirtuin6 Interactions Responsible for Mitochondrial Downregulation in Aging Tunicates. Molecular and cellular biology 17 33875574
2001 Functional interaction of Yaf2 with the central region of MycN. Oncogene 15 11593398
2022 Salidroside alleviates severe acute pancreatitis-triggered pancreatic injury and inflammation by regulating miR-217-5p/YAF2 axis. International immunopharmacology 14 35963157
2021 MiR-139-5p Targetedly Regulates YAF2 and Mediates the AKT/P38 MAPK Signaling Pathway to Alleviate the Metastasis of Non-Small Cell Lung Cancer Cells and Their Resistance Against Cisplatin. Cancer management and research 14 33981163
2023 Functional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells. Nature communications 11 37935677
2015 YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5. Biochimica et biophysica acta 10 25603536
2018 The polycomb group protein Yaf2 regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner. The Journal of biological chemistry 9 29959227
2018 MicroRNA-543 promotes ovariectomy-induced osteoporosis through inhibition of AKT/p38 MAPK signaling pathway by targeting YAF2. Journal of cellular biochemistry 9 30506950
2003 The mouse YAF2 gene generates two distinct transcripts and is expressed in pre-and postimplantation embryos. Gene 9 14557078
2003 Yaf2 inhibits Myc biological function. Cancer letters 8 12706874
2021 YAF2 exerts anti-apoptotic effect in human tumor cells in a FANK1- and phosphorylation-dependent manner. Biochemical and biophysical research communications 5 33784512
2023 NEAT1 enhances MPP+ -induced pyroptosis in a cell model of Parkinson's disease via targeting miR-5047/YAF2 signaling. Immunity, inflammation and disease 4 37382256
2025 RETRACTION: NEAT1 Enhances MPP + -Induced Pyroptosis in a Cell Model of Parkinson's Disease via Targeting miR-5047/YAF2 Signaling. Immunity, inflammation and disease 0 40432551
2024 Exosomal miR-7-25207 Increases Subgroup J Avian Leukosis Virus Titers by Targeting the Akt-CyclinQ1 and PRC1-YAF2 Dual Pathways. Microorganisms 0 39065263

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