Affinage

YAF2

YY1-associated factor 2 · UniProt Q8IY57

Length
180 aa
Mass
19.9 kDa
Annotated
2026-04-28
22 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YAF2 is a Polycomb group (PcG) cofactor that functions as a scaffold within variant PRC1 complexes to propagate histone H2A monoubiquitination and modulate transcription factor activity. YAF2 specifically recognizes H2AK119ub1 and, as a subunit of noncanonical PRC1 (with Ring1B), catalyzes ubiquitination of H2A on neighboring nucleosomes through a positive-feedback mechanism that maintains Polycomb repression through cell division; serine 166 phosphorylation of YAF2 is required for Ring1B-mediated H2A ubiquitination and target gene repression, and Yaf2 loss in ESCs compromises proliferation and alters differentiation fate (PMID:32203418, PMID:29959227, PMID:37935677). YAF2 bridges YY1 to PRC1 via the YY1 REPO domain, enabling DNA-targeted Polycomb recruitment, and also bridges YY1 to SIRT6 to promote H3K9 deacetylation at specific promoters (PMID:24285299, PMID:19960508, PMID:33875574). Beyond chromatin regulation, YAF2 modulates transcription factor output—enhancing MycN- and hGABP-mediated transactivation while inhibiting Myc-mediated transactivation and transformation—and stabilizes PDCD5 to promote TP53-dependent apoptosis under genotoxic stress, while phosphorylated YAF2 stabilizes FANK1 to suppress apoptosis in tumor cells (PMID:11593398, PMID:12706874, PMID:25603536, PMID:33784512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 Medium

    Identifying YAF2 as a nuclear cofactor of MycN established its first role in transcriptional regulation, showing it could directly bind and enhance MycN transactivation from E-box elements.

    Evidence Yeast two-hybrid, Co-IP, nuclear co-localization, E-box reporter assays with deletion mapping

    PMID:11593398

    Open questions at the time
    • Endogenous target genes of the YAF2–MycN interaction not identified
    • Physiological relevance in neuroblastoma not tested in vivo
  2. 2002 Medium

    Demonstrating that YAF2 interacts with both hGABPβ and YY1 and positively regulates hGABP transcriptional activity revealed YAF2 as a modular transcription factor cofactor with partner-dependent activating or repressing effects.

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

    PMID:11953439

    Open questions at the time
    • Chromatin-level targets of hGABP–YAF2 not mapped
    • Structural basis of differential regulation versus YEAF1 unknown
  3. 2003 Medium

    Finding that YAF2 inhibits Myc transactivation and transformation—opposite to its enhancement of MycN—established context-dependent transcriptional modulation by YAF2, while concurrent discovery of YAF2 incorporation into Ring1B-containing PcG complexes connected it to Polycomb biology.

    Evidence Co-IP, reporter and transformation assays (Myc); biochemical pulldown and co-localization with Ring1B in tissue culture cells

    PMID:12706874 PMID:14557078

    Open questions at the time
    • Molecular basis for opposite effects on Myc versus MycN not determined
    • Composition of the YAF2-containing PcG complex not fully defined
  4. 2006 Medium

    Zebrafish morpholino studies revealed a developmental survival function for Yaf2, showing it suppresses caspase 8-mediated apoptosis during embryogenesis—a role conserved across vertebrates as demonstrated by rescue with human YAF2.

    Evidence Morpholino knockdown in zebrafish embryos, rescue with human YAF2 mRNA and caspase 8 inhibitor

    PMID:16891308

    Open questions at the time
    • Mechanism by which YAF2 inhibits caspase 8 activation not elucidated
    • Morpholino approach carries off-target risk; genetic knockout not performed
  5. 2010 Medium

    Mapping the YY1 REPO domain as the minimal 25-amino-acid element sufficient for YAF2 recruitment, and showing that YAF2 fused to a heterologous DNA-binding domain recruits PcG and mediates repression, established the molecular logic of YY1-directed Polycomb targeting through YAF2.

    Evidence Domain deletion, heterologous DBD fusion, transcriptional repression assays, Drosophila dRYBP analysis

    PMID:19960508

    Open questions at the time
    • Structure of the REPO–YAF2 interface not resolved
    • Whether all YY1-bound sites recruit PcG via YAF2 in vivo was untested
  6. 2013 High

    ChIP experiments and cross-species genetic rescue demonstrated that YAF2 bridges YY1 to PRC1 on chromatin in vivo, with YY1 DNA binding required prior to YAF2-dependent PcG assembly, establishing the order of events in DNA-targeted Polycomb recruitment.

    Evidence Co-IP, ChIP in HeLa cells, YY1 knockdown, rescue of Drosophila dRYBP mutants with mouse YAF2

    PMID:24285299

    Open questions at the time
    • Genome-wide sites of YY1–YAF2–PRC1 co-occupancy not profiled at this stage
    • Whether YAF2 is required at all PRC1 target loci or a subset unclear
  7. 2015 Medium

    Discovery that YAF2 stabilizes PDCD5 by blocking its ubiquitin-dependent proteasomal degradation, and that this is required for TP53 activation upon genotoxic stress, revealed a non-chromatin function for YAF2 in apoptotic signaling.

    Evidence Yeast two-hybrid, Co-IP, ubiquitin-proteasome assays, siRNA knockdown, genotoxic stress response assays

    PMID:25603536

    Open questions at the time
    • E3 ligase targeting PDCD5 that YAF2 antagonizes not identified
    • In vivo validation of this apoptotic axis lacking
  8. 2018 High

    Reconstitution and mutagenesis demonstrated that Ser166 phosphorylation is required for Ring1B-mediated H2A ubiquitination and that residues 102–150 mediate PRC1 assembly; Yaf2 deletion in mouse ESCs caused proliferation defects and aberrant ectoderm gene derepression, establishing YAF2 as a functional noncanonical PRC1 subunit controlling differentiation.

    Evidence Phosphosite mutagenesis (S166A), in vitro ubiquitination, genome-wide profiling, mouse ESC differentiation assays

    PMID:29959227

    Open questions at the time
    • Kinase responsible for Ser166 phosphorylation not identified
    • Whether phosphorylation is dynamically regulated during differentiation not tested
  9. 2020 High

    Biochemical reconstitution showed that YAF2 (and its paralog RYBP) directly reads H2AK119ub1 to recruit variant PRC1, which then ubiquitinates H2A on neighboring nucleosomes, establishing a positive-feedback loop for Polycomb mark propagation through cell division; histone H1-compacted chromatin enhances distal spreading.

    Evidence Binding assays, in vitro ubiquitination on nucleosome substrates, cell division inheritance experiments

    PMID:32203418

    Open questions at the time
    • Relative contributions of YAF2 versus RYBP to propagation in vivo not separated
    • Whether the feedback is self-limiting or requires additional regulation not addressed
  10. 2021 Medium

    Two independent studies expanded YAF2's scaffolding repertoire: one showed YAF2 bridges YY1 and SIRT6 (1:1:1) to drive H3K9 deacetylation at the TFAM promoter during aging; the other showed phospho-Ser167 YAF2 stabilizes FANK1 against proteasomal degradation to suppress tumor cell apoptosis.

    Evidence Pulldown/cross-linking stoichiometry, ChIP-qPCR in tunicate model (YY1–SIRT6); Co-IP, domain mapping, apoptosis assays in tumor cells (FANK1)

    PMID:33784512 PMID:33875574

    Open questions at the time
    • YY1–YAF2–SIRT6 axis validated only in tunicate; conservation in mammals not shown
    • Kinase for Ser167 not identified; relationship to Ser166 phosphorylation in PRC1 context unclear
  11. 2023 High

    Knockout comparisons in ESCs showed that YAF2 and RYBP are not redundant: Yaf2 loss promotes neural differentiation and causes RYBP redistribution with increased H2AK119ub at co-targeted genes, establishing paralog-specific and antagonistic roles in lineage decisions.

    Evidence Yaf2 and Rybp knockout ESC lines, ChIP-seq, RNA-seq, neural differentiation assays

    PMID:37935677

    Open questions at the time
    • Mechanism by which YAF2 loss leads to RYBP redistribution rather than simple loss of PRC1 occupancy not elucidated
    • In vivo developmental phenotypes of Yaf2 knockout mice not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the kinase(s) phosphorylating YAF2 at Ser166/167, the structural basis of YAF2's recognition of H2AK119ub1, how the chromatin (PRC1) and non-chromatin (PDCD5/FANK1/apoptosis) functions are coordinated, and the in vivo developmental consequences of YAF2 loss in mammals.
  • No kinase identified for Ser166/167 phosphorylation
  • No crystal or cryo-EM structure of YAF2 in any complex
  • No conditional knockout mouse phenotype reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-4839726 Chromatin organization 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2
Partners
FANK1MYCMYCNPDCD5RING1BRYBPSIRT6YY1
Complex memberships
YY1-YAF2-SIRT6 complexvariant PRC1 (noncanonical PRC1)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 YAF2 specifically binds H2AK119ub1 to recruit 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 H2AK119ub1 by RYBP/YAF2-PRC1. Biochemical binding assays, in vitro ubiquitination assays, cell division inheritance experiments, disruption of RYBP/YAF2-PRC1 activity Nature cell biology High 32203418
2013 YAF2 bridges the interaction between the transcription factor YY1 and the PRC1 complex, enabling PcG recruitment to DNA; YY1 DNA binding is required prior to YAF2-dependent PcG assembly on chromatin. Functional conservation demonstrated by rescue of Drosophila dRYBP mutants with mouse YAF2. Co-immunoprecipitation, ChIP assays in HeLa cells, YY1 knockdown, genetic rescue in Drosophila dRYBP mutants Nucleic acids research High 24285299
2010 The YY1 REPO domain (25 amino acids) directly interacts with Yaf2, recruiting it to DNA; Yaf2 linked to a heterologous DNA-binding domain can recruit PcG proteins to DNA and mediate transcriptional repression; deletion of REPO domain abolishes interaction. Domain deletion analysis, heterologous DNA-binding domain fusion assay, transcriptional repression assays, Drosophila dRYBP mutation analysis Journal of cellular biochemistry Medium 19960508
2002 YAF2 interacts with both hGABPβ and YY1 in vitro and in vivo; YAF2 positively regulates transcriptional activity of hGABP, while its paralog YEAF1 negatively regulates it; YEAF1 bridges hGABPβ and YY1 into a complex, as shown by yeast three-hybrid assay. Yeast two-hybrid screening, yeast three-hybrid assay, in vitro and in vivo binding assays, transcriptional activity assays The Journal of biological chemistry Medium 11953439
2015 YAF2 binds PDCD5 and increases PDCD5 protein stability by inhibiting ubiquitin-dependent proteasomal degradation; upon genotoxic stress, YAF2 promotes TP53 activation via its association with PDCD5; YAF2 cannot promote TP53 activation without PDCD5. Yeast two-hybrid screen, Co-immunoprecipitation, ubiquitin-proteasome assays, siRNA knockdown, genotoxic stress response assays, PDCD5 deletion/mutation experiments Biochimica et biophysica acta Medium 25603536
2018 Yaf2 assembles into a noncanonical PRC1 complex; residues 102-150 are required for this assembly. Serine 166 phosphorylation of Yaf2 is required for Ring1B-mediated H2A monoubiquitination and target gene repression; S166A mutation compromises these activities. Yaf2 deletion causes compromised proliferation and abnormal differentiation of mouse ESCs, with Yaf2 acting primarily as a transcriptional repressor for ectoderm-associated genes. Deletion analysis, phosphorylation site mutagenesis (S166A), genome-wide profiling, in vitro ubiquitination assays, mouse ESC differentiation assays The Journal of biological chemistry High 29959227
2023 RYBP and YAF2 have distinct regulatory functions in neural differentiation of ESCs: Rybp knockout impairs neural differentiation by activating Wnt signaling, while Yaf2 knockout promotes neural differentiation and leads to redistribution of RYBP binding and increased H2AK119ub enrichment on co-targeted genes. Knockout ESC lines, ChIP-seq, RNA-seq, neural differentiation assays, genome-wide profiling Nature communications High 37935677
2001 Yaf2 binds the central region of MycN in vitro and in vivo, co-localizes with MycN in 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-IP, nuclear localization (microscopy), E-box reporter transactivation assay, deletion analysis Oncogene Medium 11593398
2003 Yaf2 binds Myc protein in vivo and in vitro; in contrast to its activating effect on MycN, Yaf2 inhibits Myc-mediated transactivation and transformation. In vitro binding assay, in vivo Co-IP, transcriptional reporter assay, transformation assay Cancer letters Medium 12706874
2003 Mouse YAF2 protein interacts with Ring1B (and Ring1A), co-localizes with Ring1B in tissue culture cells, and is incorporated into PcG complexes; the YAF2 locus generates two distinct isoforms by alternative splicing. Biochemical pulldown, co-localization studies in tissue culture cells, alternative splicing analysis Gene Medium 14557078
2006 Yaf2 functions as a survival factor during early zebrafish embryogenesis by inhibiting caspase 8-mediated apoptosis; depletion of zYaf2 activates widespread caspase 8-dependent apoptosis, which is rescued by human YAF2 mRNA or caspase 8-specific inhibitor. Morpholino knockdown in zebrafish, rescue with human YAF2 mRNA, pan-caspase and caspase 8-specific inhibitor treatment, apoptosis assays in cultured cells The Journal of biological chemistry Medium 16891308
2021 YAF2 mediates the interaction between YY1 and SIRT6; YAF2 bridges YY1 and SIRT6 with a 1:1:1 molar ratio, and this complex promotes SIRT6-dependent H3K9 deacetylation at the TFAM gene promoter, leading to aging-related mitochondrial downregulation in tunicates. Pulldown assays, protein cross-linking, ChIP-qPCR, mRNA co-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 it (FN3 domain of FANK1 binds N-terminus of YAF2), thereby stabilizing FANK1 and suppressing tumor cell apoptosis in a FANK1-dependent manner. Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assays, domain mapping, apoptosis assays Biochemical and biophysical research communications Medium 33784512

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 91 32203418
2013 YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment. Nucleic acids research 54 24285299
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 52 35936223
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 42 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 29 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 13 33981163
2023 Functional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells. Nature communications 10 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