{"gene":"SAP30","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1998,"finding":"SAP30 is a component of the human Sin3/HDAC histone deacetylase complex that includes Sin3, HDAC1, HDAC2, RbAp46, and RbAp48. The complex is active in deacetylating core histone octamers but inactive on nucleosomal histones because RbAp46/48 cannot access nucleosomal histones. A yeast SAP30 homolog is functionally related to Sin3 and Rpd3.","method":"Biochemical purification, co-immunoprecipitation, in vitro histone deacetylase activity assay on core histones vs. nucleosomes","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — original purification with in vitro activity assay, replicated across labs","pmids":["9651585"],"is_preprint":false},{"year":1998,"finding":"SAP30 binds directly to mSin3 and mediates transcriptional repression via histone deacetylases. SAP30 also binds the N-CoR corepressor and is required for N-CoR-mediated repression by antagonist-bound estrogen receptor and homeodomain protein Rpx, and for N-CoR suppression of Pit-1 transactivation, but is not required for N-CoR-mediated repression by unliganded retinoic acid receptor or thyroid hormone receptor.","method":"Co-immunoprecipitation, GST pulldown, reporter gene repression assays, dominant-negative SAP30 experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, independent replication","pmids":["9702189"],"is_preprint":false},{"year":2003,"finding":"SAP30 associates with the transcription factor YY1 via the C-terminal 91 amino acids of SAP30 and the C-terminal segment (295-414) of YY1, enhancing YY1-mediated transcriptional repression in a dose-dependent manner. YY1, SAP30, and HDAC1 form a complex in vivo, providing a mechanism by which YY1 recruits HDAC1 indirectly through SAP30.","method":"Yeast two-hybrid, in vitro GST pulldown, in vivo co-immunoprecipitation, reporter gene assays, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in single lab with domain mapping","pmids":["12788099"],"is_preprint":false},{"year":2008,"finding":"SAP30 and SAP30L contain a zinc-coordinating structure necessary for direct binding to core histones and naked DNA, and for bending DNA. A sequence motif serving as a nuclear localization signal also functions as a phosphatidylinositol (PI)-binding element; binding of nuclear monophosphoinositides regulates DNA binding, chromatin association, repression activity, and nuclear-to-cytoplasmic translocation of SAP30L.","method":"In vitro DNA-binding assays, mutagenesis of zinc-coordinating residues, electrophoretic mobility shift assay, PI-binding assays, chromatin immunoprecipitation, confocal microscopy, reporter gene assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional assays in a single study","pmids":["19015240"],"is_preprint":false},{"year":2008,"finding":"RVFV nonstructural protein NSs interacts with SAP30, which in turn interacts with YY1. NSs, SAP30, and Sin3A-associated factors are recruited to the IFN-beta promoter through YY1, inhibiting CBP recruitment, histone acetylation, and transcriptional activation. Deletion of the NSs-SAP30 interaction domain abolished IFN-beta suppression and rendered the virus avirulent.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, chromatin immunoprecipitation, reverse genetics (recombinant virus with NSs deletion), in vivo mouse infection","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including ChIP, live imaging, and genetic rescue in vivo","pmids":["18225953"],"is_preprint":false},{"year":2009,"finding":"The solution structure of a novel CCCH zinc finger (ZnF) motif in SAP30 was determined by NMR. The ZnF adopts a fold with two beta-strands and two alpha-helices with a zinc organizing center remotely resembling the treble clef motif. NMR analysis showed the SAP30 ZnF has a strong preference for nucleic acid substrates, functioning as a double-stranded DNA-binding module.","method":"NMR structure determination, in silico surface analysis, NMR-based ligand binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional validation by nucleic acid binding assays","pmids":["19223330"],"is_preprint":false},{"year":2011,"finding":"The solution structure of the mSin3A PAH3 domain in complex with the SAP30 Sin3 interaction domain (SID) was determined by NMR. The SAP30 SID binds to PAH3 via a tripartite structural motif (C-terminal helix targeting the canonical PAH hydrophobic cleft, two other helices, and an N-terminal extension), resulting in a large protein-protein interface (~1400 Ų) accounting for constitutive association. The mSin3A PAH3-SAP30 SID complex also binds nucleic acids, implicating the nucleolar localization sequence in rRNA gene silencing.","method":"NMR structure determination, isothermal titration calorimetry, NMR-based nucleic acid binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with interface characterization and nucleic acid binding assays","pmids":["21676866"],"is_preprint":false},{"year":2007,"finding":"Papillomavirus binding factor (PBF/HDBP2) directly binds to SAP30 via amino acids 263-312 of PBF, and this interaction recruits the SIN3A-HDAC1 complex to mediate transcriptional repression. TSA (HDAC inhibitor) relieves PBF-mediated repression, demonstrating that HDAC activity is required.","method":"Co-immunoprecipitation, GST pulldown, reporter gene repression assays, TSA inhibitor treatment, domain mapping","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods in single lab with pharmacological validation","pmids":["17897615"],"is_preprint":false},{"year":2010,"finding":"RBP1 acts as a bridging protein between pRb and SAP30 (within the mSin3·HDAC complex). CDK2 phosphorylates RBP1 on serines 864 and 1007, destabilizing the RBP1-pRb interaction in vitro; concurrent phosphorylation of both RBP1 and pRb causes their dissociation, releasing the SAP30·mSin3·HDAC repressor complex from pRb to alleviate E2F transcriptional repression during G1-S progression.","method":"In vitro kinase assay, co-immunoprecipitation, mutagenesis of CDK phosphorylation sites, cell cycle synchronization, immunoprecipitation from MCF-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphorylation reconstitution with mutagenesis and cell-based validation","pmids":["21148318"],"is_preprint":false},{"year":2010,"finding":"In the nucleus, SLy2 (SAMSN1/HACS1) interacts with the SAP30/HDAC1 complex and regulates HDAC1 activity. Phosphorylated SLy2 is retained in the cytoplasm by 14-3-3 proteins, controlling its nuclear access and thus its regulation of the SAP30/HDAC1 complex.","method":"Co-immunoprecipitation, subcellular fractionation, protein interaction assays, HDAC activity assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional HDAC assay in single lab","pmids":["20478393"],"is_preprint":false},{"year":2022,"finding":"UHRF1 directly interacts with SAP30 through two critical amino acids (G572 and F573) in its SRA domain to repress gene expression. This UHRF1-SAP30 interaction is required for myeloid leukemogenesis; depletion of either UHRF1 or SAP30 derepresses MXD4 (a MYC antagonist), suppressing leukemia-initiating cell self-renewal.","method":"Co-immunoprecipitation, mutagenesis of UHRF1 SRA domain, shRNA knockdown, rescue experiments, chromatin immunoprecipitation, PDX mouse model","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including mutagenesis, ChIP, and in vivo validation","pmids":["36302855"],"is_preprint":false},{"year":2023,"finding":"SAP30 forms a homodimer with one subunit binding to SIN3A/3B and another recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. This SAP30-MLL1 interaction is required for SAP30-mediated transcriptional coactivation (enhancing chromatin accessibility and RNA Pol II occupancy at promoters) and breast tumor progression, independent of the canonical SIN3-HDAC gene silencing function.","method":"Co-immunoprecipitation, mutagenesis of Phe186/200, chromatin immunoprecipitation, ATAC-seq, RNA Pol II ChIP-seq, breast cancer mouse models, rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis, genome-wide chromatin assays, and in vivo models","pmids":["37655663"],"is_preprint":false},{"year":2024,"finding":"SAP30 transcriptionally regulates STX17 (a SNARE protein required for autophagosome-lysosome fusion). Silencing SAP30 decreases STX17 expression, inhibits its translocation to the autophagic membrane, and blocks autophagosome-lysosome fusion, thereby inhibiting autophagy in neuroblastoma cells.","method":"siRNA knockdown, ectopic overexpression, reporter/promoter assays, western blotting, confocal microscopy, in vivo xenograft and PDX models","journal":"Molecular therapy. Oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss- and gain-of-function with mechanistic downstream target identification in single lab","pmids":["40190355"],"is_preprint":false},{"year":2025,"finding":"SAP30 interacts with the prototype foamy virus Tas transactivator protein and induces its deacetylation, thereby suppressing Tas-mediated transactivation of PFV LTR and internal promoters. The Sin3 interaction domain (SID) at the C-terminus of SAP30 is the critical domain for inhibiting PFV transcription. PFV infection also upregulates SAP30 via Tas-mediated enhancement of the SAP30 promoter.","method":"Co-immunoprecipitation, overexpression and knockdown experiments, promoter-reporter assays, acetylation assays, domain deletion analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods in single lab with domain-level mechanistic resolution","pmids":["40275313"],"is_preprint":false},{"year":2025,"finding":"SAP30 mRNA is upregulated in colorectal cancer via METTL14-mediated m6A modification of SAP30 mRNA, which is recognized and stabilized by the m6A reader YTHDF1. Elevated SAP30 promotes glycolysis (upregulating LDHA, HK1, HK2, GLUT1, GLUT4) and oxaliplatin resistance; SAP30 knockout impairs tumor growth in vivo.","method":"m6A methylation assays, RIP (RNA immunoprecipitation), siRNA/overexpression, glycolysis assays, in vivo xenograft, GLUT1 inhibitor rescue","journal":"Journal of gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-level modification mechanism identified with multiple functional readouts in single lab","pmids":["40289460"],"is_preprint":false},{"year":2009,"finding":"Phylogenetic and biochemical analysis shows that SAP30 has diverged functionally from its paralog SAP30L by accumulating mutations that attenuate association with the nuclear matrix. This function is mediated by a nuclear matrix association sequence consisting of a conserved C-terminal motif adjacent to a nucleolar localization signal (NoLS).","method":"Phylogenetic sequence analysis, biochemical nuclear matrix association assays","journal":"BMC evolutionary biology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single biochemical method with evolutionary inference","pmids":["19566944"],"is_preprint":false}],"current_model":"SAP30 is a constitutive core subunit of the evolutionarily conserved Sin3/HDAC histone deacetylase corepressor complex, where it binds directly to the mSin3A PAH3 domain via a tripartite SID motif (~1400 Ų interface), bridges additional corepressors (N-CoR, RBP1, UHRF1) and transcription factors (YY1, PBF) to the complex, contains a CCCH zinc finger that mediates direct DNA and nucleosome binding, and can also act as a transcriptional coactivator by forming a homodimer that recruits MLL1 through Phe186/200 residues; its activity and complex association are regulated by CDK2-mediated phosphorylation of the bridging protein RBP1, by nuclear phosphoinositide binding, and by m6A mRNA modification, enabling SAP30 to control diverse transcriptional programs including IFN-beta suppression, cell cycle progression, autophagy (via STX17), and oncogenesis."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of SAP30 as a subunit of the Sin3/HDAC complex established it as an integral component of histone deacetylase-based transcriptional repression, resolving how this complex is assembled from multiple protein partners.","evidence":"Biochemical purification and co-immunoprecipitation of the human Sin3/HDAC complex with in vitro deacetylase activity assays","pmids":["9651585"],"confidence":"High","gaps":["Specific contribution of SAP30 versus other subunits to complex assembly unknown","No structural data on SAP30 at this stage"]},{"year":1998,"claim":"Demonstration that SAP30 directly bridges N-CoR to the Sin3 complex and is selectively required for repression by specific nuclear receptors revealed it as a pathway-specific adaptor rather than a generic complex subunit.","evidence":"Co-IP, GST pulldown, reporter gene assays, and dominant-negative SAP30 experiments with estrogen receptor, Rpx, and Pit-1","pmids":["9702189"],"confidence":"High","gaps":["Structural basis for selectivity among different nuclear receptor pathways not resolved","No genome-wide target identification"]},{"year":2003,"claim":"Mapping the SAP30–YY1 interaction showed how a sequence-specific transcription factor recruits HDAC1 indirectly through SAP30, establishing SAP30 as a bridge between DNA-bound factors and the deacetylase machinery.","evidence":"Yeast two-hybrid, GST pulldown, in vivo co-IP, reporter assays, and domain mapping of YY1 and SAP30","pmids":["12788099"],"confidence":"Medium","gaps":["Endogenous genomic targets of YY1–SAP30 repression not identified","No structural resolution of the YY1–SAP30 interface"]},{"year":2007,"claim":"The discovery that PBF directly binds SAP30 to recruit SIN3A-HDAC1 extended the repertoire of transcription factors that use SAP30 as a HDAC-recruiting adaptor.","evidence":"Co-IP, GST pulldown, reporter assays with TSA inhibitor validation, domain mapping","pmids":["17897615"],"confidence":"Medium","gaps":["Physiological gene targets of PBF–SAP30 repression unknown","No in vivo validation"]},{"year":2008,"claim":"Identification of SAP30's zinc-coordinating module as a DNA/histone-binding domain and its nuclear localization signal as a phosphoinositide-binding element revealed dual regulatory inputs — chromatin engagement and lipid-mediated nucleocytoplasmic control — previously unknown for any Sin3 complex subunit.","evidence":"EMSA, mutagenesis of zinc-coordinating residues, PI-binding assays, ChIP, confocal microscopy, reporter assays","pmids":["19015240"],"confidence":"High","gaps":["Identity of specific nuclear PI species regulating SAP30 in vivo not determined","Functional distinction between SAP30 and SAP30L DNA binding not fully resolved"]},{"year":2008,"claim":"Demonstration that the Rift Valley fever virus NSs protein hijacks SAP30–YY1 to suppress IFN-beta transcription provided the first evidence that SAP30's bridging function is co-opted by a pathogen to subvert innate immunity.","evidence":"Yeast two-hybrid, co-IP, ChIP at IFN-beta promoter, confocal microscopy, recombinant virus with NSs deletion, mouse infection model","pmids":["18225953"],"confidence":"High","gaps":["Whether SAP30 is required for IFN-beta repression in non-viral contexts not tested","No structure of NSs–SAP30 interface"]},{"year":2009,"claim":"The NMR solution structure of the SAP30 CCCH zinc finger as a novel treble-clef-like fold with strong dsDNA preference provided atomic-level understanding of how SAP30 engages chromatin.","evidence":"NMR structure determination with NMR-based ligand binding assays","pmids":["19223330"],"confidence":"High","gaps":["No structure in complex with DNA","Specificity for particular DNA sequences not determined"]},{"year":2010,"claim":"CDK2-mediated phosphorylation of RBP1 was shown to release the SAP30·Sin3·HDAC complex from pRb, linking SAP30-dependent repression to cell cycle control at the G1-S transition.","evidence":"In vitro kinase assay, co-IP, phosphosite mutagenesis, cell cycle synchronization in MCF-7 cells","pmids":["21148318"],"confidence":"High","gaps":["Direct consequences of complex release on E2F target gene expression not measured genome-wide","Whether SAP30 itself is phosphorylated during the cell cycle not addressed"]},{"year":2011,"claim":"The NMR structure of the mSin3A PAH3–SAP30 SID complex revealed a tripartite binding mode with a ~1400 Ų interface, explaining SAP30's constitutive association with Sin3 and its ability to simultaneously bind nucleic acids for rRNA gene silencing.","evidence":"NMR structure determination, ITC, NMR-based nucleic acid binding assays","pmids":["21676866"],"confidence":"High","gaps":["rRNA gene silencing function not validated genome-wide","Whether SAP30 binding occludes other Sin3 PAH3 partners not tested"]},{"year":2022,"claim":"UHRF1 was shown to recruit SAP30 via its SRA domain (G572/F573) to repress MXD4, establishing a SAP30-dependent epigenetic axis essential for myeloid leukemia-initiating cell self-renewal.","evidence":"Co-IP, SRA domain mutagenesis, shRNA knockdown with rescue, ChIP, PDX mouse models","pmids":["36302855"],"confidence":"High","gaps":["Full set of UHRF1–SAP30 co-regulated genes not defined","Whether UHRF1–SAP30 interaction depends on DNA methylation status not tested"]},{"year":2023,"claim":"Discovery of SAP30 homodimerization and MLL1 recruitment through Phe186/200 revealed a SIN3-independent coactivation function, overturning the view that SAP30 acts exclusively as a corepressor.","evidence":"Co-IP, Phe186/200 mutagenesis, ChIP, ATAC-seq, RNA Pol II ChIP-seq, breast cancer mouse models with rescue","pmids":["37655663"],"confidence":"High","gaps":["How the balance between corepressor and coactivator functions is regulated is unknown","Whether the homodimer can simultaneously engage Sin3 and MLL1 at the same locus not resolved"]},{"year":2024,"claim":"SAP30 was found to transcriptionally regulate STX17, coupling its corepressor/coactivator function to autophagosome-lysosome fusion and autophagy in neuroblastoma.","evidence":"siRNA knockdown, overexpression, promoter-reporter assays, confocal microscopy, xenograft and PDX models","pmids":["40190355"],"confidence":"Medium","gaps":["Whether SAP30 directly binds the STX17 promoter via its zinc finger or acts through an intermediary is unclear","Generalizability beyond neuroblastoma not tested"]},{"year":2025,"claim":"Two studies extended SAP30 biology in distinct directions: its SID-dependent deacetylation and suppression of foamy virus Tas transactivator, and its post-transcriptional regulation via METTL14-mediated m6A modification stabilized by YTHDF1 driving glycolysis and drug resistance in colorectal cancer.","evidence":"Co-IP, domain deletion, acetylation assays, promoter-reporter for PFV; m6A-RIP, siRNA/overexpression, glycolysis assays, xenograft for CRC","pmids":["40275313","40289460"],"confidence":"Medium","gaps":["Endogenous glycolytic gene targets directly bound by SAP30 in CRC not identified by ChIP","Whether SAP30-mediated Tas deacetylation occurs in natural foamy virus infection unknown","Functional interplay between m6A-driven SAP30 upregulation and its coactivator vs. corepressor modes not explored"]},{"year":null,"claim":"It remains unknown how the switch between SAP30's corepressor (Sin3/HDAC) and coactivator (MLL1) functions is regulated at specific genomic loci, and whether phosphoinositide binding, post-translational modifications, or homodimerization dynamics govern this decision.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide map of SAP30-bound loci distinguishing repressive from activating complexes","Post-translational modification landscape of SAP30 itself largely uncharacterized","No full-length structure of SAP30 in either complex context"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,7,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,6,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6,15]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3,8,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,7,11,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,14]}],"complexes":["Sin3/HDAC complex","SAP30 homodimer-MLL1 complex"],"partners":["SIN3A","HDAC1","NCOR1","YY1","UHRF1","MLL1","RBP1","SAMSN1"],"other_free_text":[]},"mechanistic_narrative":"SAP30 is a constitutive core subunit of the Sin3/HDAC histone deacetylase corepressor complex that functions as a multivalent scaffold bridging sequence-specific transcription factors, chromatin, and additional corepressors to regulate diverse transcriptional programs. SAP30 binds the mSin3A PAH3 domain through a tripartite SID motif forming a ~1400 Ų interface [PMID:21676866], contains a CCCH zinc finger that directly binds double-stranded DNA and core histones [PMID:19015240, PMID:19223330], and recruits transcription factors (YY1, PBF) and corepressors (N-CoR, UHRF1) to the complex to mediate gene silencing at specific loci including IFN-beta and the MYC antagonist MXD4 [PMID:9702189, PMID:12788099, PMID:18225953, PMID:36302855]. Beyond its canonical corepressor role, SAP30 forms a homodimer in which one subunit engages SIN3A/3B while the other recruits MLL1 through Phe186/200 residues, enabling a SIN3-independent transcriptional coactivation function that promotes breast tumor progression [PMID:37655663]. SAP30 activity is regulated by nuclear phosphoinositide binding, which modulates its DNA binding and chromatin association [PMID:19015240], and its mRNA abundance is controlled by METTL14-mediated m6A modification recognized by YTHDF1 [PMID:40289460]."},"prefetch_data":{"uniprot":{"accession":"O75446","full_name":"Histone deacetylase complex subunit SAP30","aliases":["30 kDa Sin3-associated polypeptide","Sin3 corepressor complex subunit SAP30","Sin3-associated polypeptide p30"],"length_aa":220,"mass_kda":23.3,"function":"Involved in the functional recruitment of the Sin3-histone deacetylase complex (HDAC) to a specific subset of N-CoR corepressor complexes. Capable of transcription repression by N-CoR. Active in deacetylating core histone octamers (when in a complex) but inactive in deacetylating nucleosomal histones (Microbial infection) Involved in transcriptional repression of HHV-1 genes TK and gC","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75446/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SAP30","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":4.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SAP30","total_profiled":1310},"omim":[{"mim_id":"618514","title":"BRMS1-LIKE TRANSCRIPTIONAL REPRESSOR; BRMS1L","url":"https://www.omim.org/entry/618514"},{"mim_id":"610398","title":"SAP30-LIKE PROTEIN; SAP30L","url":"https://www.omim.org/entry/610398"},{"mim_id":"610218","title":"SAP30-BINDING PROTEIN; SAP30BP","url":"https://www.omim.org/entry/610218"},{"mim_id":"609697","title":"SIN3A-ASSOCIATED PROTEIN, 130-KD; SAP130","url":"https://www.omim.org/entry/609697"},{"mim_id":"608250","title":"SDS3 HOMOLOG, SIN3A COREPRESSOR COMPLEX COMPONENT; SUDS3","url":"https://www.omim.org/entry/608250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SAP30"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75446","domains":[{"cath_id":"3.40.1800.30","chopping":"70-125","consensus_level":"high","plddt":82.7236,"start":70,"end":125},{"cath_id":"-","chopping":"150-209","consensus_level":"medium","plddt":84.4482,"start":150,"end":209}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75446","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75446-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75446-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAP30","jax_strain_url":"https://www.jax.org/strain/search?query=SAP30"},"sequence":{"accession":"O75446","fasta_url":"https://rest.uniprot.org/uniprotkb/O75446.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75446/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75446"}},"corpus_meta":[{"pmid":"9651585","id":"PMC_9651585","title":"SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9651585","citation_count":250,"is_preprint":false},{"pmid":"9702189","id":"PMC_9702189","title":"SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9702189","citation_count":187,"is_preprint":false},{"pmid":"18225953","id":"PMC_18225953","title":"A SAP30 complex inhibits IFN-beta expression in Rift Valley fever virus infected cells.","date":"2008","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/18225953","citation_count":175,"is_preprint":false},{"pmid":"19015240","id":"PMC_19015240","title":"DNA-binding and -bending activities of SAP30L and SAP30 are mediated by a zinc-dependent module and monophosphoinositides.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19015240","citation_count":49,"is_preprint":false},{"pmid":"36302855","id":"PMC_36302855","title":"Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.","date":"2022","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36302855","citation_count":34,"is_preprint":false},{"pmid":"15005689","id":"PMC_15005689","title":"Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes.","date":"2004","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15005689","citation_count":32,"is_preprint":false},{"pmid":"21676866","id":"PMC_21676866","title":"Structure of the 30-kDa Sin3-associated protein (SAP30) in complex with the mammalian Sin3A corepressor and its role in nucleic acid binding.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21676866","citation_count":31,"is_preprint":false},{"pmid":"12788099","id":"PMC_12788099","title":"Modulation of YY1 activity by SAP30.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12788099","citation_count":31,"is_preprint":false},{"pmid":"21148318","id":"PMC_21148318","title":"Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30·mSin3·HDAC transcriptional repressor complex.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21148318","citation_count":21,"is_preprint":false},{"pmid":"17897615","id":"PMC_17897615","title":"Papillomavirus binding factor binds to SAP30 and represses transcription via recruitment of the HDAC1 co-repressor complex.","date":"2007","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/17897615","citation_count":20,"is_preprint":false},{"pmid":"20478393","id":"PMC_20478393","title":"SLy2 targets the nuclear SAP30/HDAC1 complex.","date":"2010","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20478393","citation_count":15,"is_preprint":false},{"pmid":"19223330","id":"PMC_19223330","title":"Solution structure of a novel zinc finger motif in the SAP30 polypeptide of the Sin3 corepressor complex and its potential role in nucleic acid recognition.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19223330","citation_count":14,"is_preprint":false},{"pmid":"11087671","id":"PMC_11087671","title":"Mouse scrapie responsive gene 1 (Scrg1): genomic organization, physical linkage to sap30, genetic mapping on chromosome 8, and expression in neuronal primary cell cultures.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11087671","citation_count":14,"is_preprint":false},{"pmid":"32820380","id":"PMC_32820380","title":"Long non-coding RNA SAP30-2:1 is downregulated in congenital heart disease and regulates cell proliferation by targeting HAND2.","date":"2020","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32820380","citation_count":12,"is_preprint":false},{"pmid":"19566944","id":"PMC_19566944","title":"Phylogenetic analysis of the SAP30 family of transcriptional regulators reveals functional divergence in the domain that binds the nuclear matrix.","date":"2009","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/19566944","citation_count":10,"is_preprint":false},{"pmid":"37655663","id":"PMC_37655663","title":"SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37655663","citation_count":8,"is_preprint":false},{"pmid":"38154101","id":"PMC_38154101","title":"Reveal the correlation between hub hypoxia/immune-related genes and immunity and diagnosis, and the effect of SAP30 on cell apoptosis, ROS and MDA production in cerebral ischemic stroke.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38154101","citation_count":4,"is_preprint":false},{"pmid":"40289460","id":"PMC_40289460","title":"The METTL14-YTHDF1-SAP30 Axis Promotes Glycolysis and Oxaliplatin Resistance in Colorectal Adenocarcinoma via m6A Modification.","date":"2025","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40289460","citation_count":1,"is_preprint":false},{"pmid":"40190355","id":"PMC_40190355","title":"SAP30, a novel autophagy regulatory gene in neuroblastoma.","date":"2024","source":"Molecular therapy. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40190355","citation_count":0,"is_preprint":false},{"pmid":"40275313","id":"PMC_40275313","title":"SAP30 deacetylates the Tas protein to inhibit PFV replication.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/40275313","citation_count":0,"is_preprint":false},{"pmid":"40247376","id":"PMC_40247376","title":"SAP30 promotes clear cell renal cell carcinoma proliferation and inhibits apoptosis through the MT1G axis.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/40247376","citation_count":0,"is_preprint":false},{"pmid":"34646299","id":"PMC_34646299","title":"SAP30 Gene Is a Probable Regulator of Muscle Hypertrophy in Chickens.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34646299","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.08.650247","title":"Formation of chromosomal rearrangements in <i>Saccharomyces cerevisiae</i> diploids through regionally-biased non-allelic homologous recombination","date":"2025-05-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.650247","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11474,"output_tokens":4189,"usd":0.048628},"stage2":{"model":"claude-opus-4-6","input_tokens":7630,"output_tokens":3492,"usd":0.188175},"total_usd":0.236803,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SAP30 is a component of the human Sin3/HDAC histone deacetylase complex that includes Sin3, HDAC1, HDAC2, RbAp46, and RbAp48. The complex is active in deacetylating core histone octamers but inactive on nucleosomal histones because RbAp46/48 cannot access nucleosomal histones. A yeast SAP30 homolog is functionally related to Sin3 and Rpd3.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, in vitro histone deacetylase activity assay on core histones vs. nucleosomes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original purification with in vitro activity assay, replicated across labs\",\n      \"pmids\": [\"9651585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SAP30 binds directly to mSin3 and mediates transcriptional repression via histone deacetylases. SAP30 also binds the N-CoR corepressor and is required for N-CoR-mediated repression by antagonist-bound estrogen receptor and homeodomain protein Rpx, and for N-CoR suppression of Pit-1 transactivation, but is not required for N-CoR-mediated repression by unliganded retinoic acid receptor or thyroid hormone receptor.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter gene repression assays, dominant-negative SAP30 experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, independent replication\",\n      \"pmids\": [\"9702189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAP30 associates with the transcription factor YY1 via the C-terminal 91 amino acids of SAP30 and the C-terminal segment (295-414) of YY1, enhancing YY1-mediated transcriptional repression in a dose-dependent manner. YY1, SAP30, and HDAC1 form a complex in vivo, providing a mechanism by which YY1 recruits HDAC1 indirectly through SAP30.\",\n      \"method\": \"Yeast two-hybrid, in vitro GST pulldown, in vivo co-immunoprecipitation, reporter gene assays, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab with domain mapping\",\n      \"pmids\": [\"12788099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SAP30 and SAP30L contain a zinc-coordinating structure necessary for direct binding to core histones and naked DNA, and for bending DNA. A sequence motif serving as a nuclear localization signal also functions as a phosphatidylinositol (PI)-binding element; binding of nuclear monophosphoinositides regulates DNA binding, chromatin association, repression activity, and nuclear-to-cytoplasmic translocation of SAP30L.\",\n      \"method\": \"In vitro DNA-binding assays, mutagenesis of zinc-coordinating residues, electrophoretic mobility shift assay, PI-binding assays, chromatin immunoprecipitation, confocal microscopy, reporter gene assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional assays in a single study\",\n      \"pmids\": [\"19015240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RVFV nonstructural protein NSs interacts with SAP30, which in turn interacts with YY1. NSs, SAP30, and Sin3A-associated factors are recruited to the IFN-beta promoter through YY1, inhibiting CBP recruitment, histone acetylation, and transcriptional activation. Deletion of the NSs-SAP30 interaction domain abolished IFN-beta suppression and rendered the virus avirulent.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, chromatin immunoprecipitation, reverse genetics (recombinant virus with NSs deletion), in vivo mouse infection\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, live imaging, and genetic rescue in vivo\",\n      \"pmids\": [\"18225953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The solution structure of a novel CCCH zinc finger (ZnF) motif in SAP30 was determined by NMR. The ZnF adopts a fold with two beta-strands and two alpha-helices with a zinc organizing center remotely resembling the treble clef motif. NMR analysis showed the SAP30 ZnF has a strong preference for nucleic acid substrates, functioning as a double-stranded DNA-binding module.\",\n      \"method\": \"NMR structure determination, in silico surface analysis, NMR-based ligand binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional validation by nucleic acid binding assays\",\n      \"pmids\": [\"19223330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The solution structure of the mSin3A PAH3 domain in complex with the SAP30 Sin3 interaction domain (SID) was determined by NMR. The SAP30 SID binds to PAH3 via a tripartite structural motif (C-terminal helix targeting the canonical PAH hydrophobic cleft, two other helices, and an N-terminal extension), resulting in a large protein-protein interface (~1400 Ų) accounting for constitutive association. The mSin3A PAH3-SAP30 SID complex also binds nucleic acids, implicating the nucleolar localization sequence in rRNA gene silencing.\",\n      \"method\": \"NMR structure determination, isothermal titration calorimetry, NMR-based nucleic acid binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with interface characterization and nucleic acid binding assays\",\n      \"pmids\": [\"21676866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Papillomavirus binding factor (PBF/HDBP2) directly binds to SAP30 via amino acids 263-312 of PBF, and this interaction recruits the SIN3A-HDAC1 complex to mediate transcriptional repression. TSA (HDAC inhibitor) relieves PBF-mediated repression, demonstrating that HDAC activity is required.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter gene repression assays, TSA inhibitor treatment, domain mapping\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods in single lab with pharmacological validation\",\n      \"pmids\": [\"17897615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBP1 acts as a bridging protein between pRb and SAP30 (within the mSin3·HDAC complex). CDK2 phosphorylates RBP1 on serines 864 and 1007, destabilizing the RBP1-pRb interaction in vitro; concurrent phosphorylation of both RBP1 and pRb causes their dissociation, releasing the SAP30·mSin3·HDAC repressor complex from pRb to alleviate E2F transcriptional repression during G1-S progression.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, mutagenesis of CDK phosphorylation sites, cell cycle synchronization, immunoprecipitation from MCF-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation reconstitution with mutagenesis and cell-based validation\",\n      \"pmids\": [\"21148318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the nucleus, SLy2 (SAMSN1/HACS1) interacts with the SAP30/HDAC1 complex and regulates HDAC1 activity. Phosphorylated SLy2 is retained in the cytoplasm by 14-3-3 proteins, controlling its nuclear access and thus its regulation of the SAP30/HDAC1 complex.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, protein interaction assays, HDAC activity assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional HDAC assay in single lab\",\n      \"pmids\": [\"20478393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UHRF1 directly interacts with SAP30 through two critical amino acids (G572 and F573) in its SRA domain to repress gene expression. This UHRF1-SAP30 interaction is required for myeloid leukemogenesis; depletion of either UHRF1 or SAP30 derepresses MXD4 (a MYC antagonist), suppressing leukemia-initiating cell self-renewal.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of UHRF1 SRA domain, shRNA knockdown, rescue experiments, chromatin immunoprecipitation, PDX mouse model\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including mutagenesis, ChIP, and in vivo validation\",\n      \"pmids\": [\"36302855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SAP30 forms a homodimer with one subunit binding to SIN3A/3B and another recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. This SAP30-MLL1 interaction is required for SAP30-mediated transcriptional coactivation (enhancing chromatin accessibility and RNA Pol II occupancy at promoters) and breast tumor progression, independent of the canonical SIN3-HDAC gene silencing function.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of Phe186/200, chromatin immunoprecipitation, ATAC-seq, RNA Pol II ChIP-seq, breast cancer mouse models, rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis, genome-wide chromatin assays, and in vivo models\",\n      \"pmids\": [\"37655663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SAP30 transcriptionally regulates STX17 (a SNARE protein required for autophagosome-lysosome fusion). Silencing SAP30 decreases STX17 expression, inhibits its translocation to the autophagic membrane, and blocks autophagosome-lysosome fusion, thereby inhibiting autophagy in neuroblastoma cells.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, reporter/promoter assays, western blotting, confocal microscopy, in vivo xenograft and PDX models\",\n      \"journal\": \"Molecular therapy. Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss- and gain-of-function with mechanistic downstream target identification in single lab\",\n      \"pmids\": [\"40190355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SAP30 interacts with the prototype foamy virus Tas transactivator protein and induces its deacetylation, thereby suppressing Tas-mediated transactivation of PFV LTR and internal promoters. The Sin3 interaction domain (SID) at the C-terminus of SAP30 is the critical domain for inhibiting PFV transcription. PFV infection also upregulates SAP30 via Tas-mediated enhancement of the SAP30 promoter.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown experiments, promoter-reporter assays, acetylation assays, domain deletion analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods in single lab with domain-level mechanistic resolution\",\n      \"pmids\": [\"40275313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SAP30 mRNA is upregulated in colorectal cancer via METTL14-mediated m6A modification of SAP30 mRNA, which is recognized and stabilized by the m6A reader YTHDF1. Elevated SAP30 promotes glycolysis (upregulating LDHA, HK1, HK2, GLUT1, GLUT4) and oxaliplatin resistance; SAP30 knockout impairs tumor growth in vivo.\",\n      \"method\": \"m6A methylation assays, RIP (RNA immunoprecipitation), siRNA/overexpression, glycolysis assays, in vivo xenograft, GLUT1 inhibitor rescue\",\n      \"journal\": \"Journal of gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-level modification mechanism identified with multiple functional readouts in single lab\",\n      \"pmids\": [\"40289460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Phylogenetic and biochemical analysis shows that SAP30 has diverged functionally from its paralog SAP30L by accumulating mutations that attenuate association with the nuclear matrix. This function is mediated by a nuclear matrix association sequence consisting of a conserved C-terminal motif adjacent to a nucleolar localization signal (NoLS).\",\n      \"method\": \"Phylogenetic sequence analysis, biochemical nuclear matrix association assays\",\n      \"journal\": \"BMC evolutionary biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single biochemical method with evolutionary inference\",\n      \"pmids\": [\"19566944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAP30 is a constitutive core subunit of the evolutionarily conserved Sin3/HDAC histone deacetylase corepressor complex, where it binds directly to the mSin3A PAH3 domain via a tripartite SID motif (~1400 Ų interface), bridges additional corepressors (N-CoR, RBP1, UHRF1) and transcription factors (YY1, PBF) to the complex, contains a CCCH zinc finger that mediates direct DNA and nucleosome binding, and can also act as a transcriptional coactivator by forming a homodimer that recruits MLL1 through Phe186/200 residues; its activity and complex association are regulated by CDK2-mediated phosphorylation of the bridging protein RBP1, by nuclear phosphoinositide binding, and by m6A mRNA modification, enabling SAP30 to control diverse transcriptional programs including IFN-beta suppression, cell cycle progression, autophagy (via STX17), and oncogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SAP30 is a constitutive core subunit of the Sin3/HDAC histone deacetylase corepressor complex that functions as a multivalent scaffold bridging sequence-specific transcription factors, chromatin, and additional corepressors to regulate diverse transcriptional programs. SAP30 binds the mSin3A PAH3 domain through a tripartite SID motif forming a ~1400 Ų interface [PMID:21676866], contains a CCCH zinc finger that directly binds double-stranded DNA and core histones [PMID:19015240, PMID:19223330], and recruits transcription factors (YY1, PBF) and corepressors (N-CoR, UHRF1) to the complex to mediate gene silencing at specific loci including IFN-beta and the MYC antagonist MXD4 [PMID:9702189, PMID:12788099, PMID:18225953, PMID:36302855]. Beyond its canonical corepressor role, SAP30 forms a homodimer in which one subunit engages SIN3A/3B while the other recruits MLL1 through Phe186/200 residues, enabling a SIN3-independent transcriptional coactivation function that promotes breast tumor progression [PMID:37655663]. SAP30 activity is regulated by nuclear phosphoinositide binding, which modulates its DNA binding and chromatin association [PMID:19015240], and its mRNA abundance is controlled by METTL14-mediated m6A modification recognized by YTHDF1 [PMID:40289460].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of SAP30 as a subunit of the Sin3/HDAC complex established it as an integral component of histone deacetylase-based transcriptional repression, resolving how this complex is assembled from multiple protein partners.\",\n      \"evidence\": \"Biochemical purification and co-immunoprecipitation of the human Sin3/HDAC complex with in vitro deacetylase activity assays\",\n      \"pmids\": [\"9651585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific contribution of SAP30 versus other subunits to complex assembly unknown\", \"No structural data on SAP30 at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that SAP30 directly bridges N-CoR to the Sin3 complex and is selectively required for repression by specific nuclear receptors revealed it as a pathway-specific adaptor rather than a generic complex subunit.\",\n      \"evidence\": \"Co-IP, GST pulldown, reporter gene assays, and dominant-negative SAP30 experiments with estrogen receptor, Rpx, and Pit-1\",\n      \"pmids\": [\"9702189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selectivity among different nuclear receptor pathways not resolved\", \"No genome-wide target identification\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the SAP30–YY1 interaction showed how a sequence-specific transcription factor recruits HDAC1 indirectly through SAP30, establishing SAP30 as a bridge between DNA-bound factors and the deacetylase machinery.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, in vivo co-IP, reporter assays, and domain mapping of YY1 and SAP30\",\n      \"pmids\": [\"12788099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous genomic targets of YY1–SAP30 repression not identified\", \"No structural resolution of the YY1–SAP30 interface\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The discovery that PBF directly binds SAP30 to recruit SIN3A-HDAC1 extended the repertoire of transcription factors that use SAP30 as a HDAC-recruiting adaptor.\",\n      \"evidence\": \"Co-IP, GST pulldown, reporter assays with TSA inhibitor validation, domain mapping\",\n      \"pmids\": [\"17897615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological gene targets of PBF–SAP30 repression unknown\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of SAP30's zinc-coordinating module as a DNA/histone-binding domain and its nuclear localization signal as a phosphoinositide-binding element revealed dual regulatory inputs — chromatin engagement and lipid-mediated nucleocytoplasmic control — previously unknown for any Sin3 complex subunit.\",\n      \"evidence\": \"EMSA, mutagenesis of zinc-coordinating residues, PI-binding assays, ChIP, confocal microscopy, reporter assays\",\n      \"pmids\": [\"19015240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific nuclear PI species regulating SAP30 in vivo not determined\", \"Functional distinction between SAP30 and SAP30L DNA binding not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that the Rift Valley fever virus NSs protein hijacks SAP30–YY1 to suppress IFN-beta transcription provided the first evidence that SAP30's bridging function is co-opted by a pathogen to subvert innate immunity.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, ChIP at IFN-beta promoter, confocal microscopy, recombinant virus with NSs deletion, mouse infection model\",\n      \"pmids\": [\"18225953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SAP30 is required for IFN-beta repression in non-viral contexts not tested\", \"No structure of NSs–SAP30 interface\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The NMR solution structure of the SAP30 CCCH zinc finger as a novel treble-clef-like fold with strong dsDNA preference provided atomic-level understanding of how SAP30 engages chromatin.\",\n      \"evidence\": \"NMR structure determination with NMR-based ligand binding assays\",\n      \"pmids\": [\"19223330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure in complex with DNA\", \"Specificity for particular DNA sequences not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"CDK2-mediated phosphorylation of RBP1 was shown to release the SAP30·Sin3·HDAC complex from pRb, linking SAP30-dependent repression to cell cycle control at the G1-S transition.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, phosphosite mutagenesis, cell cycle synchronization in MCF-7 cells\",\n      \"pmids\": [\"21148318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct consequences of complex release on E2F target gene expression not measured genome-wide\", \"Whether SAP30 itself is phosphorylated during the cell cycle not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The NMR structure of the mSin3A PAH3–SAP30 SID complex revealed a tripartite binding mode with a ~1400 Ų interface, explaining SAP30's constitutive association with Sin3 and its ability to simultaneously bind nucleic acids for rRNA gene silencing.\",\n      \"evidence\": \"NMR structure determination, ITC, NMR-based nucleic acid binding assays\",\n      \"pmids\": [\"21676866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"rRNA gene silencing function not validated genome-wide\", \"Whether SAP30 binding occludes other Sin3 PAH3 partners not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"UHRF1 was shown to recruit SAP30 via its SRA domain (G572/F573) to repress MXD4, establishing a SAP30-dependent epigenetic axis essential for myeloid leukemia-initiating cell self-renewal.\",\n      \"evidence\": \"Co-IP, SRA domain mutagenesis, shRNA knockdown with rescue, ChIP, PDX mouse models\",\n      \"pmids\": [\"36302855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of UHRF1–SAP30 co-regulated genes not defined\", \"Whether UHRF1–SAP30 interaction depends on DNA methylation status not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of SAP30 homodimerization and MLL1 recruitment through Phe186/200 revealed a SIN3-independent coactivation function, overturning the view that SAP30 acts exclusively as a corepressor.\",\n      \"evidence\": \"Co-IP, Phe186/200 mutagenesis, ChIP, ATAC-seq, RNA Pol II ChIP-seq, breast cancer mouse models with rescue\",\n      \"pmids\": [\"37655663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the balance between corepressor and coactivator functions is regulated is unknown\", \"Whether the homodimer can simultaneously engage Sin3 and MLL1 at the same locus not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SAP30 was found to transcriptionally regulate STX17, coupling its corepressor/coactivator function to autophagosome-lysosome fusion and autophagy in neuroblastoma.\",\n      \"evidence\": \"siRNA knockdown, overexpression, promoter-reporter assays, confocal microscopy, xenograft and PDX models\",\n      \"pmids\": [\"40190355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SAP30 directly binds the STX17 promoter via its zinc finger or acts through an intermediary is unclear\", \"Generalizability beyond neuroblastoma not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies extended SAP30 biology in distinct directions: its SID-dependent deacetylation and suppression of foamy virus Tas transactivator, and its post-transcriptional regulation via METTL14-mediated m6A modification stabilized by YTHDF1 driving glycolysis and drug resistance in colorectal cancer.\",\n      \"evidence\": \"Co-IP, domain deletion, acetylation assays, promoter-reporter for PFV; m6A-RIP, siRNA/overexpression, glycolysis assays, xenograft for CRC\",\n      \"pmids\": [\"40275313\", \"40289460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous glycolytic gene targets directly bound by SAP30 in CRC not identified by ChIP\", \"Whether SAP30-mediated Tas deacetylation occurs in natural foamy virus infection unknown\", \"Functional interplay between m6A-driven SAP30 upregulation and its coactivator vs. corepressor modes not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the switch between SAP30's corepressor (Sin3/HDAC) and coactivator (MLL1) functions is regulated at specific genomic loci, and whether phosphoinositide binding, post-translational modifications, or homodimerization dynamics govern this decision.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide map of SAP30-bound loci distinguishing repressive from activating complexes\", \"Post-translational modification landscape of SAP30 itself largely uncharacterized\", \"No full-length structure of SAP30 in either complex context\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 7, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 6, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6, 15]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3, 8, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 7, 11, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 14]}\n    ],\n    \"complexes\": [\n      \"Sin3/HDAC complex\",\n      \"SAP30 homodimer-MLL1 complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"NCOR1\",\n      \"YY1\",\n      \"UHRF1\",\n      \"MLL1\",\n      \"RBP1\",\n      \"SAMSN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}