{"gene":"ARID4A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1991,"finding":"ARID4A (RBP1) was identified as a cellular protein that directly binds to the retinoblastoma gene product pRb through a conserved LXCXE-like motif. In vitro binding assays showed RBP1 specifically binds pRb, and this interaction is disrupted by HPV-16 E7 protein and by mutations in the putative pRb-binding segment of RBP1.","method":"cDNA expression library screen with recombinant pRb, in vitro binding assay, site-directed mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — original discovery with in vitro reconstitution, mutagenesis, and competitive inhibition","pmids":["1857421"],"is_preprint":false},{"year":1993,"finding":"RBP1 (ARID4A) is a large (~200 kDa) nuclear phosphoprotein ubiquitously expressed, and forms stable complexes with pRb in vivo that are dissociated by purified HPV E7 protein. The protein undergoes alternative splicing in an internal exon containing potential casein kinase II and p34cdc2 phosphorylation sites, generating a family of RB-binding isoforms.","method":"cDNA cloning, immunoblot, co-immunoprecipitation, in vivo complex analysis, in vitro RB-binding assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP in vivo, replicated by two papers (PMID:8414517, PMID:8455946)","pmids":["8414517","8455946"],"is_preprint":false},{"year":1999,"finding":"RBP1 (ARID4A) functions as a transcriptional corepressor that recruits both HDAC-dependent and HDAC-independent repression activities to the pRb family pocket. RBP1 contains two repression domains: one (R2) binds all three known HDACs (HDAC1, HDAC2, HDAC3) and represses transcription in an HDAC-dependent manner; the other functions independently of HDACs. Overexpression of RBP1 inhibits E2F-mediated transcription and suppresses cell growth.","method":"Transcriptional repression assays, co-immunoprecipitation, HDAC activity assays, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, functional domain mapping with repression assays","pmids":["10490602","10321733"],"is_preprint":false},{"year":1998,"finding":"RBP1 (ARID4A) is a component of the mSIN3-SAP30-HDAC complex. SAP30 was identified as a component of a human histone deacetylase complex that includes Sin3, HDAC1/2, and RBP1 as a bridging factor connecting pRb to this repressor complex.","method":"Biochemical purification, co-immunoprecipitation, mass spectrometry identification of complex components","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — biochemical purification and co-IP establishing complex membership","pmids":["9651585"],"is_preprint":false},{"year":2001,"finding":"RBP1 (ARID4A) recruits the mSIN3-SAP30-HDAC complex (containing exclusively class I HDACs) to the pRb family pocket via the LXCXE motif. In quiescent normal human cells, the entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with RB family members and E2F4 in discrete nuclear regions corresponding to initial origins of DNA replication. RBP1 accounts for the majority of RB-associated HDAC activity.","method":"Co-immunoprecipitation, immunofluorescence colocalization, HDAC activity assays, cell fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (co-IP, imaging, enzymatic assay) in a single rigorous study","pmids":["11283269"],"is_preprint":false},{"year":2003,"finding":"BRMS1 (breast cancer metastasis suppressor 1) interacts with ARID4A (RBP1) and at least seven members of the mSIN3 HDAC complex in human breast and melanoma cell lines. BRMS1 co-immunoprecipitates enzymatically active HDAC proteins and exists in large mSIN3 complexes (~1.4–1.9 MDa). ARID4A is thus a component of a SIN3-HDAC chromatin remodeling complex involved in metastasis suppression.","method":"Yeast two-hybrid, co-immunoprecipitation, gel filtration, transcriptional repression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus reciprocal co-IP plus enzymatic activity, multiple cell lines","pmids":["14581478"],"is_preprint":false},{"year":2003,"finding":"SAP180, a protein 40% identical to RBP1/ARID4A, was identified as a novel mSIN3A-associated protein. RBP1 itself is confirmed as a component of the mSIN3A corepressor complex; all SAPs (including RBP1) bind to the HDAC-interaction domain (HID) of mSIN3A, suggesting that the HID functions as an assembly interface for the mSIN3A corepressor complex.","method":"Biochemical purification from K562 cells, co-immunoprecipitation, gel filtration, transcriptional repression assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — biochemical purification plus functional repression assays, domain mapping","pmids":["12724404"],"is_preprint":false},{"year":2006,"finding":"RBP1 (ARID4A) family members exhibit SUMOylation-dependent transcriptional repression. The R1 repression region contains a SUMOylated moiety (R1σ) that represses both basal and activated transcription in a SUMOylation-dependent manner, and an alpha-helical region (R1α) embedded within the ARID domain that represses only basal transcription. Overexpression of RBP1 causes profound inhibition of cell proliferation and induces expression of a senescence marker, requiring both R1 and R2 domains.","method":"Transcriptional repression assays, SUMOylation analysis, cell proliferation/senescence assays, domain deletion analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, domain mapping with functional validation","pmids":["16479010"],"is_preprint":false},{"year":2006,"finding":"Rbbp1/Arid4a and Rbbp1l1/Arid4b regulate genomic imprinting at the PWS/AS domain. RBBP1/ARID4A physically interacts with RBBP1L1/ARID4B and with the Snrpn promoter. Combined homozygous deficiency for Arid4a and heterozygous deficiency for Arid4b altered epigenetic modifications at the PWS-IC, reducing trimethylation of histone H4K20 and H3K9 and reducing DNA methylation. Mutations in Arid4a, Arid4b, or Rb suppressed an AS imprinting defect.","method":"Gene trap mutagenesis, mouse knockout, chromatin immunoprecipitation, western blot, immunofluorescence, genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — mouse knockout with multiple epigenetic readouts, genetic epistasis with Rb pathway","pmids":["17043311"],"is_preprint":false},{"year":2008,"finding":"SIRT1 negatively regulates HDAC1-dependent transcriptional repression by RBP1 (ARID4A). The HDAC-dependent R2 domain of RBP1 is necessary and sufficient for interaction with SIRT1. The ING1b and ING2 subunits of the mSIN3A/HDAC1 complex recruit SIRT1 to the R2 domain. SIRT1 activity inhibits R2-mediated mSIN3A/HDAC1 transcriptional repression, establishing a class III HDAC regulatory mechanism over class I HDAC activity.","method":"In vitro and in vivo binding assays, transcriptional repression assays with sirtuin activator (resveratrol) and inhibitor (sirtinol), domain mapping","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple binding assays plus pharmacological perturbation in functional repression assays","pmids":["18193082"],"is_preprint":false},{"year":2008,"finding":"Arid4a functions as a leukemia suppressor gene. Arid4a-deficient mice develop ineffective hematopoiesis, transition to CMML-like myelodysplastic/myeloproliferative disorder, and then AML. Arid4a deficiency causes increased trimethylation of H3K4, H3K9, and H4K20 in bone marrow. Hox gene expression (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3 are reduced in Arid4a-deficient bone marrow.","method":"Mouse knockout, complete blood counts, flow cytometry, histology, RT-PCR, western blot, immunofluorescence","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined hematopoietic phenotype and molecular mechanism (histone marks, target genes)","pmids":["18728284"],"is_preprint":false},{"year":2008,"finding":"BRMS1 interaction with ARID4A is required for specific aspects of SIN3-HDAC complex function. BRMS1(L174D) disrupts direct ARID4A interaction in yeast two-hybrid but retains indirect association by co-IP; BRMS1(ΔCC1) prevents co-IP association. These mutations alter complex composition, impair basal transcription repression, and differentially regulate osteopontin, but both mutants still suppress metastasis by downregulating EGFR.","method":"Yeast two-hybrid, co-immunoprecipitation, gene expression analysis, xenograft metastasis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but focused on BRMS1 mutants; ARID4A role inferred","pmids":["18211900"],"is_preprint":false},{"year":2010,"finding":"CDK2 phosphorylates RBP1 (ARID4A) on serines 864 and 1007 (flanking the LXCXE motif). CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, and concurrent phosphorylation of both proteins causes their dissociation, releasing the mSIN3-HDAC transcriptional repressor complex from pRb. RBP1 phosphorylation increases during G1-to-S phase progression in MCF-7 cells.","method":"In vitro kinase assay, in vitro binding assay, cell cycle synchronization, co-immunoprecipitation, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus cell-cycle-correlated co-IP","pmids":["21148318"],"is_preprint":false},{"year":2013,"finding":"ARID4A and ARID4B physically interact with each other and are required for male fertility. In Sertoli cells, ARID4A and ARID4B function as transcriptional coactivators for androgen receptor (AR) and RB, regulating AR- and RB-responsive genes. Their combined deficiency causes spermatogenic arrest, impaired blood-testis barrier integrity, hypogonadism, and seminal vesicle agenesis, phenocopying Sertoli cell-specific AR and RB knockouts.","method":"Mouse knockout, co-immunoprecipitation (ARID4A-ARID4B interaction), RT-PCR analysis of downstream targets, histology, barrier permeability assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — mouse KO with specific phenotypic readouts, co-IP for physical interaction, genetic epistasis with AR and RB pathways","pmids":["23487765"],"is_preprint":false},{"year":2018,"finding":"ARID4A and ARID4B are direct target genes of microRNA-30d in prostate cancer. Knockout of ARID4A and ARID4B promotes PCa cell proliferation, migration, and invasion in vitro, indicating a tumor suppressor function.","method":"Luciferase reporter assay (miR-30d targeting), CRISPR/siRNA knockdown, cell proliferation/migration/invasion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with cellular phenotype but no pathway placement beyond miR-30d targeting","pmids":["29797600"],"is_preprint":false},{"year":2018,"finding":"The chromo barrel domain of RBBP1 (ARID4A) was crystallized. Structural analysis indicates it could interact with histone H4K20me3 similarly to other chromo barrel domains, but ITC assays showed DNA does not significantly enhance H4K20me3 binding by the isolated chromo barrel domain, and the domain lacks a typical DNA-binding surface.","method":"X-ray crystallography, isothermal titration calorimetry (ITC)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 method (crystal structure + ITC) but only the isolated domain studied; functional consequences not established","pmids":["29408527"],"is_preprint":false},{"year":2021,"finding":"The tandem PWWP-ARID domain structure of RBBP1 (ARID4A) was determined by NMR. The ARID domain binds DNA without AT-rich or GC-rich sequence preference. A long flexible acidic loop L12 within the ARID domain acts as a DNA mimic, binding to the ARID DNA-binding region and inhibiting DNA binding in cis. Loop L12 also binds weakly to Tudor and chromo barrel domains of RBBP1, and more strongly to histone H2A-H2B. Both L12 and DNA enhance the chromo barrel domain's binding to H3K4me3 and H4K20me3, supporting a model of coordinated chromatin recognition.","method":"NMR structure determination, NMR titration, isothermal titration calorimetry, domain deletion analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus multiple binding assays with functional validation of loop L12 as DNA mimic","pmids":["34506790"],"is_preprint":false},{"year":2022,"finding":"A missense variant ARID4A p.His411Asp was identified in schizophrenia patients. The crystal structure of the PWWP-ARID tandem domain at 2.05 Å resolution revealed that PWWP and ARID form a structural supramodule. The p.His411Asp mutant adopts a less compact conformation, exhibits weaker dsDNA-binding, decreases G0-G1 cell cycle arrest, and promotes HEK293T cell proliferation, linking ARID4A's DNA-binding function to G1 cell cycle arrest.","method":"Whole-exome sequencing, X-ray crystallography (2.05 Å), DNA-binding assays, cell cycle analysis, cell proliferation assay, mutagenesis","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis, DNA-binding assays, and cell cycle functional readout","pmids":["35365808"],"is_preprint":false},{"year":2025,"finding":"ARID4A (Arid4a) functions as an RNA-binding protein that stabilizes transcripts of metastasis-suppressing genes including MTSS1, TIMP2, Rb1, and PTEN by binding to a conserved structural RNA element in their 3'UTRs. The ARID domain of Arid4a is required for this mRNA stabilization activity. Loss of Arid4a promotes breast tumor metastasis in vitro and in vivo.","method":"RNA immunoprecipitation (RIP), RIP-ChIP, EMSA, luciferase assay, mRNA stability assay, in vitro/in vivo metastasis experiments","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 — RIP plus EMSA plus mRNA stability assays establish direct RNA binding; single lab, novel finding","pmids":["40066676"],"is_preprint":false},{"year":2025,"finding":"HERC2 binds to ARID4A through a 'DxDKDxD' motif recognized by the RLD2 domain of HERC2, identifying ARID4A as one of a small set of HERC2-interacting proteins relevant to brain development.","method":"Quantitative binding assays, X-ray crystallography, sequence conservation analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 method but preprint, single study, ARID4A is one of many identified interactors without specific functional follow-up","pmids":[],"is_preprint":true},{"year":2005,"finding":"A survey of DNA-binding properties across the ARID family showed that ARID4A's ARID domain, like most ARID subfamily members, binds DNA without obvious sequence preference (not restricted to AT-rich sequences). DNA-binding affinity varies between subfamilies, and site-specific mutagenesis did not support specific amino acid determinants in Loop 2 or Helix 5 as primary drivers of sequence specificity.","method":"In vitro DNA-binding assays, site-specific mutagenesis across ARID family","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — systematic in vitro binding assays across family members with mutagenesis","pmids":["15640446"],"is_preprint":false}],"current_model":"ARID4A (RBBP1) is a large nuclear phosphoprotein that binds pRb family members via an LXCXE motif and serves as a bridging molecule recruiting the mSIN3-SAP30-HDAC corepressor complex to repress E2F-dependent transcription; its two repression domains (R1, SUMOylation-dependent; R2, HDAC-dependent via SAP30) mediate growth arrest and cellular senescence, CDK2 phosphorylation of RBP1 at S864/S1007 dissociates it from pRb to relieve repression at G1-S, SIRT1 recruited by ING proteins negatively regulates its HDAC-dependent repression, and ARID4A additionally functions as an RNA-binding protein stabilizing metastasis-suppressor transcripts through 3'UTR elements, while its tandem PWWP-ARID supramodule engages chromatin through DNA-independent and -dependent histone modification recognition."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing that ARID4A is a direct pRb-binding protein revealed a new class of pocket-protein interactor and raised the question of what effector function ARID4A brings to the Rb pathway.","evidence":"cDNA expression library screen with recombinant pRb, in vitro binding with mutagenesis and E7 competition","pmids":["1857421"],"confidence":"High","gaps":["No indication of ARID4A's transcriptional or enzymatic function","Binding site on pRb not precisely mapped"]},{"year":1998,"claim":"Identification of ARID4A as a subunit of the mSIN3–SAP30–HDAC complex answered how pRb achieves HDAC-dependent gene silencing—ARID4A acts as the physical bridge recruiting this corepressor complex to the pocket domain.","evidence":"Biochemical purification of the mSIN3A complex from human cells, co-immunoprecipitation, mass spectrometry","pmids":["9651585","10490602","10321733"],"confidence":"High","gaps":["Stoichiometry and architecture of the ARID4A–mSIN3–HDAC holocomplex unresolved","Relative contribution of R1 vs R2 repression domains to growth suppression not yet dissected"]},{"year":2001,"claim":"Demonstrating that the entire ARID4A–mSIN3–HDAC complex colocalizes with pRb/E2F4 at replication origins in quiescent cells placed ARID4A at a defined nuclear site and implied a role in DNA replication licensing control.","evidence":"Co-IP, immunofluorescence colocalization, HDAC activity assays, and cell fractionation in quiescent human fibroblasts","pmids":["11283269"],"confidence":"High","gaps":["Direct role at replication origins not tested by functional assays","Whether ARID4A is required for replication origin silencing remains untested"]},{"year":2003,"claim":"Identification of BRMS1 and SAP180 (ARID4B) as ARID4A interaction partners expanded the mSIN3 complex membership and connected ARID4A to metastasis suppression and paralog redundancy.","evidence":"Yeast two-hybrid, reciprocal co-IP, gel filtration in breast cancer and melanoma lines; biochemical purification from K562 cells","pmids":["14581478","12724404"],"confidence":"High","gaps":["Functional distinction between ARID4A and ARID4B within the complex unclear","Whether BRMS1–ARID4A interaction is essential for metastasis suppression not resolved until later mutant studies"]},{"year":2006,"claim":"Dissection of ARID4A's two repression domains revealed that R1 acts through SUMOylation and R2 through HDAC recruitment, and both are required for growth arrest and senescence—answering how a single protein enforces dual modes of transcriptional silencing.","evidence":"SUMOylation assays, transcriptional repression assays, domain deletions, cell proliferation and senescence marker analysis","pmids":["16479010"],"confidence":"High","gaps":["Identity of SUMO E3 ligase targeting R1 unknown","Endogenous genomic targets repressed by R1 vs R2 not determined"]},{"year":2006,"claim":"Mouse genetic studies showed ARID4A cooperates with ARID4B and Rb to maintain imprinting at the PWS/AS locus through histone H3K9/H4K20 trimethylation and DNA methylation, extending its role from transcriptional repression to epigenetic imprint maintenance.","evidence":"Gene-trap mutagenesis, compound Arid4a/Arid4b knockout mice, ChIP for histone marks, genetic suppression of AS imprinting defect","pmids":["17043311"],"confidence":"High","gaps":["Which histone methyltransferase is recruited by ARID4A not identified","Whether imprinting role is direct or mediated through global Rb pathway not resolved"]},{"year":2008,"claim":"Two key regulatory inputs were identified: CDK2 phosphorylation at S864/S1007 dissociates ARID4A from pRb to relieve repression at G1–S, while SIRT1 recruited by ING proteins antagonizes R2-mediated HDAC1 repression, establishing how cell cycle and sirtuin signaling converge on the ARID4A–Rb axis.","evidence":"In vitro kinase assay with mutagenesis, cell-cycle-synchronized co-IP (CDK2); binding assays with sirtuin activator/inhibitor (SIRT1)","pmids":["21148318","18193082"],"confidence":"High","gaps":["Whether CDK2 phosphorylation occurs in vivo on endogenous ARID4A not confirmed by phospho-specific antibody","How SIRT1-mediated deacetylation specifically inactivates R2 mechanistically unclear"]},{"year":2008,"claim":"Arid4a knockout mice developed myelodysplastic disorder progressing to AML with altered H3K4/H3K9/H4K20 trimethylation and deregulated Hox gene expression, establishing ARID4A as a bona fide leukemia suppressor.","evidence":"Arid4a-null mice, complete blood counts, flow cytometry, histology, RT-PCR, histone mark western blots","pmids":["18728284"],"confidence":"High","gaps":["Whether leukemia suppression is Rb-dependent or reflects Rb-independent ARID4A functions not determined","Direct target genes driving leukemogenesis upon ARID4A loss not comprehensively mapped"]},{"year":2013,"claim":"Discovery that ARID4A and ARID4B function as transcriptional coactivators for the androgen receptor in Sertoli cells, with their loss phenocopying AR and Rb knockouts, revealed a tissue-specific coactivator role beyond the canonical corepressor paradigm.","evidence":"Sertoli cell-specific compound knockout mice, co-IP for ARID4A–ARID4B interaction, RT-PCR of AR/Rb target genes, histology and barrier assays","pmids":["23487765"],"confidence":"High","gaps":["Mechanism by which ARID4A switches from corepressor to coactivator not identified","Whether direct AR interaction occurs or is mediated by Rb not tested"]},{"year":2021,"claim":"Structural determination of the PWWP–ARID supramodule by NMR revealed that an internal acidic loop (L12) acts as a DNA mimic, auto-inhibiting DNA binding and allosterically enhancing chromo barrel recognition of H3K4me3 and H4K20me3, providing a mechanistic basis for coordinated chromatin engagement.","evidence":"NMR structure, NMR titration, ITC, domain deletion analysis","pmids":["34506790"],"confidence":"High","gaps":["Whether L12 autoinhibition is relieved by post-translational modifications in vivo unknown","Which genomic loci require loop L12-mediated regulation not mapped"]},{"year":2022,"claim":"A schizophrenia-associated missense variant (p.His411Asp) in the PWWP–ARID supramodule was shown to destabilize the domain, reduce DNA binding, and impair G1 arrest, linking ARID4A chromatin engagement to a neuropsychiatric phenotype.","evidence":"Crystal structure at 2.05 Å, DNA-binding assays, cell cycle and proliferation assays on wild-type vs mutant, whole-exome sequencing of schizophrenia cohort","pmids":["35365808"],"confidence":"High","gaps":["Causality of the variant in schizophrenia not established by family segregation or animal model","Whether the structural defect affects histone-mark recognition in addition to DNA binding not tested"]},{"year":2025,"claim":"Demonstration that ARID4A is an RNA-binding protein that stabilizes metastasis-suppressor transcripts (MTSS1, TIMP2, Rb1, PTEN) via conserved 3′UTR elements expanded its functional repertoire beyond chromatin-directed transcriptional regulation to post-transcriptional mRNA stability control.","evidence":"RIP, RIP-ChIP, EMSA, luciferase 3′UTR reporters, mRNA stability assays, in vivo breast cancer metastasis model","pmids":["40066676"],"confidence":"Medium","gaps":["RNA-binding specificity determinants within the ARID domain not structurally resolved","Whether RNA binding is independent of or competitive with DNA/chromatin binding untested","Single-lab finding awaiting independent replication"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for ARID4A's switch between corepressor and coactivator functions, the identity of SUMO E3 ligases and histone methyltransferases it recruits, the full repertoire of RNA targets and whether RNA and DNA binding are mutually exclusive, and whether ARID4A's roles in leukemia suppression and imprinting are Rb-dependent or autonomous.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted holocomplex structure available","Genome-wide direct target map by ChIP-seq in a physiological context not reported","In vivo validation of RNA-binding function in development/disease models lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,4,7,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[16,17,20]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[18]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,8,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,7,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,14]}],"complexes":["mSIN3A–HDAC corepressor complex","pRb–E2F repressor complex"],"partners":["RB1","SIN3A","SAP30","HDAC1","HDAC2","ARID4B","BRMS1","SIRT1"],"other_free_text":[]},"mechanistic_narrative":"ARID4A is a nuclear transcriptional corepressor that bridges the retinoblastoma protein (pRb) to the mSIN3–SAP30–HDAC chromatin-remodeling complex, thereby repressing E2F-dependent transcription and enforcing G1 cell-cycle arrest and cellular senescence [PMID:1857421, PMID:9651585, PMID:11283269, PMID:16479010]. It harbors two repression domains—R1, which operates through SUMOylation-dependent mechanisms, and R2, which recruits class I HDACs via SAP30—and CDK2-mediated phosphorylation at S864/S1007 dissociates ARID4A from pRb at the G1–S transition, relieving repression [PMID:16479010, PMID:21148318]. Beyond transcriptional repression, ARID4A regulates genomic imprinting at the PWS/AS locus through modulation of histone methylation and DNA methylation, acts as a leukemia and metastasis suppressor whose loss causes myeloid malignancy in mice, and functions as an RNA-binding protein that stabilizes metastasis-suppressor transcripts via 3′UTR elements [PMID:17043311, PMID:18728284, PMID:40066676]. Its tandem PWWP–ARID supramodule binds DNA without sequence preference and coordinately engages modified histones (H3K4me3, H4K20me3), with an internal acidic loop acting as a DNA mimic to regulate chromatin association [PMID:34506790, PMID:35365808]."},"prefetch_data":{"uniprot":{"accession":"P29374","full_name":"AT-rich interactive domain-containing protein 4A","aliases":["Retinoblastoma-binding protein 1","RBBP-1"],"length_aa":1257,"mass_kda":142.8,"function":"DNA-binding protein which modulates activity of several transcription factors including RB1 (retinoblastoma-associated protein) and AR (androgen receptor) (By similarity). May function as part of an mSin3A repressor complex (PubMed:14581478). Has no intrinsic transcriptional activity (By similarity). Plays a role in the regulation of epigenetic modifications at the PWS/AS imprinting center near the SNRPN promoter, where it might function as part of a complex with RB1 and ARID4B (By similarity). Involved in spermatogenesis, together with ARID4B, where it acts as a transcriptional coactivator for AR and enhances expression of genes required for sperm maturation. Regulates expression of the tight junction protein CLDN3 in the testis, which is important for integrity of the blood-testis barrier (By similarity). Plays a role in myeloid homeostasis where it regulates the histone methylation state of bone marrow cells and expression of various genes involved in hematopoiesis. May function as a leukemia suppressor (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P29374/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARID4A","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARID4A","total_profiled":1310},"omim":[{"mim_id":"618514","title":"BRMS1-LIKE TRANSCRIPTIONAL REPRESSOR; BRMS1L","url":"https://www.omim.org/entry/618514"},{"mim_id":"609696","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 4B; ARID4B","url":"https://www.omim.org/entry/609696"},{"mim_id":"606259","title":"BRMS1 TRANSCRIPTIONAL REPRESSOR AND ANOIKIS REGULATOR; BRMS1","url":"https://www.omim.org/entry/606259"},{"mim_id":"604215","title":"INHIBITOR OF GROWTH 2; ING2","url":"https://www.omim.org/entry/604215"},{"mim_id":"180201","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 4A; ARID4A","url":"https://www.omim.org/entry/180201"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARID4A"},"hgnc":{"alias_symbol":["RBP1","RBP-1"],"prev_symbol":["RBBP1"]},"alphafold":{"accession":"P29374","domains":[{"cath_id":"2.30.30","chopping":"13-123","consensus_level":"medium","plddt":86.2627,"start":13,"end":123},{"cath_id":"2.30.30.140","chopping":"168-261","consensus_level":"medium","plddt":86.0346,"start":168,"end":261},{"cath_id":"1.10.150.60","chopping":"265-275_308-410","consensus_level":"medium","plddt":89.4449,"start":265,"end":410},{"cath_id":"2.30.30.140","chopping":"577-628","consensus_level":"medium","plddt":93.1069,"start":577,"end":628}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29374","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29374-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29374-F1-predicted_aligned_error_v6.png","plddt_mean":56.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARID4A","jax_strain_url":"https://www.jax.org/strain/search?query=ARID4A"},"sequence":{"accession":"P29374","fasta_url":"https://rest.uniprot.org/uniprotkb/P29374.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29374/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29374"}},"corpus_meta":[{"pmid":"11283269","id":"PMC_11283269","title":"RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11283269","citation_count":160,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8414517","id":"PMC_8414517","title":"Characterization of the retinoblastoma binding proteins RBP1 and RBP2.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8414517","citation_count":156,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14581478","id":"PMC_14581478","title":"Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastoma-binding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14581478","citation_count":141,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10490602","id":"PMC_10490602","title":"RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10490602","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19714238","id":"PMC_19714238","title":"The cyst nematode SPRYSEC protein RBP-1 elicits Gpa2- and RanGAP2-dependent plant cell death.","date":"2009","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/19714238","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7664738","id":"PMC_7664738","title":"The Drosophila SR protein RBP1 contributes to the regulation of doublesex alternative splicing by recognizing RBP1 RNA target sequences.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7664738","citation_count":104,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24382590","id":"PMC_24382590","title":"Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24382590","citation_count":101,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1340470","id":"PMC_1340470","title":"The Drosophila RNA-binding protein RBP1 is localized to transcriptionally active sites of chromosomes and shows a functional similarity to human splicing factor ASF/SF2.","date":"1992","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/1340470","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17043311","id":"PMC_17043311","title":"Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/17043311","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18728284","id":"PMC_18728284","title":"Identification of chromatin remodeling genes Arid4a and Arid4b as leukemia suppressor genes.","date":"2008","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/18728284","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10321733","id":"PMC_10321733","title":"RBP1 induces growth arrest by repression of E2F-dependent transcription.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10321733","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23487765","id":"PMC_23487765","title":"ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23487765","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1425596","id":"PMC_1425596","title":"A system to study transcription by yeast RNA polymerase I within the chromosomal context: functional analysis of the ribosomal DNA enhancer and the RBP1/REB1 binding sites.","date":"1992","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/1425596","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18193082","id":"PMC_18193082","title":"SIRT1 negatively regulates HDAC1-dependent transcriptional repression by the RBP1 family of proteins.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18193082","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19288010","id":"PMC_19288010","title":"Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma.","date":"2009","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19288010","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17698176","id":"PMC_17698176","title":"Expression analysis and RNA localization of PAI-RBP1 (SERBP1) in epithelial ovarian cancer: association with tumor progression.","date":"2007","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17698176","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2928844","id":"PMC_2928844","title":"Regional mapping of RBP4 to 10q23----q24 and RBP1 to 3q21----q22 in man.","date":"1989","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2928844","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16479010","id":"PMC_16479010","title":"RBP1 family proteins exhibit SUMOylation-dependent transcriptional repression and induce cell growth inhibition reminiscent of senescence.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16479010","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32587255","id":"PMC_32587255","title":"The RBP1-CKAP4 axis activates oncogenic autophagy and promotes cancer progression in oral squamous cell carcinoma.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32587255","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15961996","id":"PMC_15961996","title":"Negative feedback regulation among SR splicing factors encoded by Rbp1 and Rbp1-like in Drosophila.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15961996","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34990753","id":"PMC_34990753","title":"MicroRNA-20a-5p inhibits the autophagy and cisplatin resistance in ovarian cancer via regulating DNMT3B-mediated DNA methylation of RBP1.","date":"2022","source":"Reproductive toxicology (Elmsford, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/34990753","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12535708","id":"PMC_12535708","title":"Identification and polymorphism of Plasmodium vivax RBP-1 peptides which bind specifically to reticulocytes.","date":"2002","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/12535708","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10191085","id":"PMC_10191085","title":"Closing in on the BPES gene on 3q23: mapping of a de Novo reciprocal translocation t(3;4)(q23;p15.2) breakpoint within a 45-kb cosmid and mapping of three candidate genes, RBP1, RBP2, and beta'-COP, distal to the breakpoint.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10191085","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8325883","id":"PMC_8325883","title":"An RNA-binding protein gene (RBP1) of Saccharomyces cerevisiae encodes a putative glucose-repressible protein containing two RNA recognition motifs.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8325883","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8990170","id":"PMC_8990170","title":"In vivo analysis of the functional domains of the Drosophila splicing regulator RBP1.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8990170","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1563628","id":"PMC_1563628","title":"Cloning and sequence analysis of a rapamycin-binding protein-encoding gene (RBP1) from Candida albicans.","date":"1992","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/1563628","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21460086","id":"PMC_21460086","title":"Role of Rbp1 in the acquired chill-light tolerance of cyanobacteria.","date":"2011","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/21460086","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17101798","id":"PMC_17101798","title":"The doublesex splicing enhancer components Tra2 and Rbp1 also repress splicing through an intronic silencer.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17101798","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"20509905","id":"PMC_20509905","title":"Retinoblastoma binding protein-1 (RBP1) is a Runx2 coactivator and promotes osteoblastic differentiation.","date":"2010","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/20509905","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22373659","id":"PMC_22373659","title":"Differential expression of PAI-RBP1, C1orf142, and COTL1 in non-small cell lung cancer cell lines with different tumor metastatic potential.","date":"2012","source":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research","url":"https://pubmed.ncbi.nlm.nih.gov/22373659","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31277943","id":"PMC_31277943","title":"The SR proteins SF2 and RBP1 regulate triglyceride storage in the fat body of Drosophila.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31277943","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8455946","id":"PMC_8455946","title":"Alternative splicing of the RBP1 gene clusters in an internal exon that encodes potential phosphorylation sites.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8455946","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16873370","id":"PMC_16873370","title":"Estrogen receptor isoform-specific regulation of the retinoblastoma-binding protein 1 (RBBP1) gene: roles of AF1 and enhancer elements.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16873370","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29797600","id":"PMC_29797600","title":"Downregulation of ARID4A and ARID4B promote tumor progression and directly regulated by microRNA-30d in patient with prostate cancer.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29797600","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22192092","id":"PMC_22192092","title":"The evolution of the Gp-Rbp-1 gene in Globodera pallida includes multiple selective replacements.","date":"2011","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22192092","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8619318","id":"PMC_8619318","title":"A 43.5 kb segment of yeast chromosome XIV, which contains MFA2, MEP2, CAP/SRV2, NAM9, FKB1/FPR1/RBP1, MOM22 and CPT1, predicts an adenosine deaminase gene and 14 new open reading frames.","date":"1995","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8619318","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25495582","id":"PMC_25495582","title":"Structural and biochemical analysis of the Hordeum vulgare L. HvGR-RBP1 protein, a glycine-rich RNA-binding protein involved in the regulation of barley plant development and stress response.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25495582","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8665950","id":"PMC_8665950","title":"CTBP1/RBP1, a Saccharomyces cerevisiae protein which binds to T-rich single-stranded DNA containing the 11-bp core sequence of autonomously replicating sequence, is a poly(deoxypyrimidine)-binding protein.","date":"1996","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8665950","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23601377","id":"PMC_23601377","title":"Evolution and variability of Solanum RanGAP2, a cofactor in the incompatible interaction between the resistance protein GPA2 and the Globodera pallida effector Gp-RBP-1.","date":"2013","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/23601377","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30195942","id":"PMC_30195942","title":"Functional haplotypes of ARID4A affect promoter activity and semen quality of bulls.","date":"2018","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/30195942","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19731076","id":"PMC_19731076","title":"Molecular cloning and expression analysis of Bmrbp1 , the Bombyx mori homologue of the Drosophila gene rbp1.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19731076","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34506790","id":"PMC_34506790","title":"Structural Insight into Chromatin Recognition by Multiple Domains of the Tumor Suppressor RBBP1.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34506790","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10496363","id":"PMC_10496363","title":"Cytotoxic T lymphocytes that recognize decameric peptide sequences of retinoblastoma binding protein 1 (RBP-1) associated with human breast cancer.","date":"1999","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10496363","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36970364","id":"PMC_36970364","title":"Coronary artery disease-associated immune gene RBP1 and its pan-cancer analysis.","date":"2023","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36970364","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21067480","id":"PMC_21067480","title":"Screening genes of the visual cycle RGR, RBP1 and RBP3 identifies rare sequence variations.","date":"2010","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21067480","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35365808","id":"PMC_35365808","title":"A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35365808","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29408527","id":"PMC_29408527","title":"Crystal structure of chromo barrel domain of RBBP1.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29408527","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37694492","id":"PMC_37694492","title":"ELOA promotes tumor growth and metastasis by activating RBP1 in gastric cancer.","date":"2023","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37694492","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23417794","id":"PMC_23417794","title":"¹H, ¹³C, ¹⁵N backbone and side chain NMR resonance assignments for the N-terminal RNA recognition motif of the HvGR-RBP1 protein involved in the regulation of barley (Hordeum vulgare L.) senescence.","date":"2013","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/23417794","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30666492","id":"PMC_30666492","title":"Resonance assignments for the tandem PWWP-ARID domains of human RBBP1.","date":"2019","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/30666492","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41035422","id":"PMC_41035422","title":"CircSPINT2 confers sensitivity to osimertinib via hsa-miR-1296-3p/RBP1 axis and inhibits NSCLC progression.","date":"2025","source":"Molecular therapy. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41035422","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27449001","id":"PMC_27449001","title":"The 5' untranslated region of the rbp1 mRNA is required for translation of its mRNA under low temperatures in the cyanobacterium Synechococcus elongatus.","date":"2016","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27449001","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40066676","id":"PMC_40066676","title":"Arid4a Suppresses Breast Tumor Metastasis by Enhancing MTSS1 Expression via mRNA Stability.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40066676","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41514095","id":"PMC_41514095","title":"Knockdown of the fly spliceosome component Rbp1 (orthologue of SRSF1) extends lifespan.","date":"2026","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/41514095","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9338114","id":"PMC_9338114","title":"Assignment of the cellular retinol binding protein 1 (Rbp1) and hepatic lipase (Lipc) genes to rat chromosome 8.","date":"1997","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/9338114","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.09.16.670041","title":"Structural analysis of HERC2/UBE3A and HERC2/DOCK10 complexes provides new insights into the molecular basis of Angelman, Angelman-like and Dup15q Syndromes","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.16.670041","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.09.18.677196","title":"Knockdown of the fly spliceosome component <i>Rbp1</i>(orthologue of <i>SRSF1</i>) extends lifespan","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.677196","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.12.09.627542","title":"Pol II degradation activates cell death independently from the loss of transcription","date":"2024-12-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.09.627542","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.07.09.602696","title":"The RRM domain-containing protein Rbp3 interacts with ribosomes and the 3′ ends of mRNAs encoding photosynthesis proteins","date":"2024-07-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.09.602696","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15302935","id":"PMC_15302935","title":"Large-scale characterization of HeLa cell nuclear phosphoproteins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15302935","citation_count":1159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9660940","id":"PMC_9660940","title":"A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9660940","citation_count":575,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16387653","id":"PMC_16387653","title":"ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16387653","citation_count":550,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1857421","id":"PMC_1857421","title":"Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1857421","citation_count":324,"is_preprint":false,"source_track":"gene2pubmed"},{"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,"source_track":"gene2pubmed"},{"pmid":"23752268","id":"PMC_23752268","title":"The functional interactome landscape of the human histone deacetylase family.","date":"2013","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/23752268","citation_count":235,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25281560","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15640446","id":"PMC_15640446","title":"DNA-binding properties of ARID family proteins.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15640446","citation_count":200,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30804502","id":"PMC_30804502","title":"H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30804502","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12724404","id":"PMC_12724404","title":"Identification and characterization of three new components of the mSin3A corepressor complex.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12724404","citation_count":151,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35140242","id":"PMC_35140242","title":"Human transcription factor protein interaction networks.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35140242","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25609649","id":"PMC_25609649","title":"Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.","date":"2015","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/25609649","citation_count":120,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33637726","id":"PMC_33637726","title":"Combinatorial CRISPR screen identifies fitness effects of gene paralogues.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33637726","citation_count":106,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29911972","id":"PMC_29911972","title":"The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29911972","citation_count":102,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30021884","id":"PMC_30021884","title":"Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.","date":"2018","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30021884","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28986522","id":"PMC_28986522","title":"Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28986522","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35013218","id":"PMC_35013218","title":"EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013218","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32694731","id":"PMC_32694731","title":"Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.","date":"2020","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32694731","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28242625","id":"PMC_28242625","title":"ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28242625","citation_count":67,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18211900","id":"PMC_18211900","title":"Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18211900","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31352,"output_tokens":4797,"usd":0.083005},"stage2":{"model":"claude-opus-4-6","input_tokens":8264,"output_tokens":3832,"usd":0.20568},"total_usd":0.607572,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":44092,"output_tokens":6723,"usd":0.11656},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9342,"output_tokens":3527,"usd":0.202327}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"ARID4A (RBP1) is a large (~200 kDa) nuclear phosphoprotein that binds directly to the retinoblastoma protein pRB via the pRB pocket domain; this interaction is dissociated by HPV E7 protein, confirming it is an LXCXE-type pocket interaction. RBP1 complexes with pRB can be co-immunoprecipitated from cells.\",\n      \"method\": \"cDNA cloning, co-immunoprecipitation from cell lysates, HPV E7 competition assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional competition, replicated across multiple subsequent studies\",\n      \"pmids\": [\"8414517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"RBP1 (ARID4A) undergoes alternative splicing clustered within a 207-nucleotide internal exon that encodes potential casein kinase II and p34cdc2 phosphorylation sites, producing a family of RB-binding isoforms; all isoforms can precipitate pRB from cell lysates but cannot bind mutant RB, demonstrating the pocket-binding specificity.\",\n      \"method\": \"cDNA and genomic cloning, in vitro pRB binding/precipitation assays, immunoblot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay with mutagenesis context (mutant RB), single study\",\n      \"pmids\": [\"8455946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RBP1 (ARID4A) contains two distinct repression domains: one (R2) recruits all three known class I HDACs (HDAC1/2/3) and mediates HDAC-dependent transcriptional repression, while a second domain functions independently of HDACs. RBP1 thereby bridges pRB family pocket proteins to both HDAC-dependent and HDAC-independent repression activities.\",\n      \"method\": \"Domain-deletion analysis, transcriptional repression assays, HDAC binding assays in transfected cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain dissection with functional assays, replicated in subsequent studies\",\n      \"pmids\": [\"10490602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of RBP1 (ARID4A) inhibits E2F-dependent gene expression and suppresses cell growth; RBP1 associates specifically with p130-E2F and pRB-E2F complexes during growth arrest, establishing RBP1 as a corepressor that induces growth arrest via pRB family members.\",\n      \"method\": \"Co-immunoprecipitation, E2F reporter assays, cell growth suppression assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP + reporter + growth assay), replicated across labs\",\n      \"pmids\": [\"10321733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RBP1 (ARID4A) forms a stable complex with the mSIN3-SAP30-HDAC complex (containing exclusively class I HDACs) and recruits it to pRB family pocket proteins; this entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with pRB family members and E2F4 in discrete nuclear regions corresponding to early DNA replication origins in quiescent cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, nuclear fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus localization, high-citation foundational study\",\n      \"pmids\": [\"11283269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BRMS1 (breast cancer metastasis suppressor 1) interacts with RBP1 (ARID4A) and at least seven members of the mSIN3 HDAC complex, co-immunoprecipitating enzymatically active HDAC proteins; BRMS1 exists in large (~1.4–1.9 MDa) mSIN3 complexes containing RBP1, placing RBP1 as a scaffold within this repressor complex.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, HDAC activity assay, transcriptional repression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by Co-IP plus enzymatic activity, multiple orthogonal methods\",\n      \"pmids\": [\"14581478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBP1 (ARID4A) family proteins exhibit SUMOylation-dependent transcriptional repression: the R1 region contains an ARID-embedded R1alpha subdomain that represses basal transcription only, and an R1sigma subdomain whose repression activity depends on SUMOylation. Overexpression of RBP1 causes profound inhibition of cell proliferation with senescence marker induction, requiring both R1 and R2 domains.\",\n      \"method\": \"Domain-deletion mutagenesis, transcriptional repression assays, cell proliferation assays, senescence marker analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis + functional assays with multiple orthogonal readouts\",\n      \"pmids\": [\"16479010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBBP1/ARID4A interacts with RBBP1L1/ARID4B and with the Snrpn promoter, forming part of a protein complex. Combined homozygous deficiency of Rbbp1/Arid4a and heterozygous deficiency of Rbbp1l1/Arid4b in mice reduced trimethylation of histone H4K20 and H3K9 and reduced DNA methylation at the PWS-IC, shifting the maternal allele toward a paternal epigenotype. Mutations in Rbbp1/Arid4a, Rbbp1l1/Arid4b, or Rb suppressed an Angelman syndrome imprinting defect caused by AS-IC mutation.\",\n      \"method\": \"Gene trap mutagenesis, mouse knockout, ChIP for histone modifications, bisulfite sequencing for DNA methylation, genetic epistasis with AS-IC mutation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mouse KO with multiple epigenetic readouts plus genetic epistasis, replicated across genotypes\",\n      \"pmids\": [\"17043311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Arid4a-deficient mice develop ineffective hematopoiesis, CMML-like myelodysplastic/myeloproliferative disorder, and AML. Loss of Arid4a causes increased histone trimethylation of H3K4, H3K9, and H4K20 in bone marrow, and decreased expression of Hox genes (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3, establishing ARID4A as a leukemia suppressor that regulates histone methylation and Hox gene expression in hematopoiesis.\",\n      \"method\": \"Mouse knockout, complete blood counts, histology, flow cytometry, western blotting for histone modifications, RT-PCR for downstream gene expression\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular phenotype, multiple molecular readouts\",\n      \"pmids\": [\"18728284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The HDAC-dependent repression domain (R2) of RBP1 (ARID4A) is necessary and sufficient for interaction with SIRT1; p33(ING1b) and p33(ING2) subunits of the mSIN3A/HDAC1 complex recruit SIRT1 to R2. SIRT1 activity negatively regulates R2-mediated transcriptional repression, establishing a class III HDAC (SIRT1) as a negative regulator of class I HDAC-dependent RBP1 repression.\",\n      \"method\": \"In vitro and in vivo binding assays, transcriptional repression assays with sirtuin activator (resveratrol) and inhibitor (sirtinol), domain-deletion analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro + in vivo binding with pharmacological modulation, multiple orthogonal approaches\",\n      \"pmids\": [\"18193082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDK2 phosphorylates RBP1 (ARID4A) on serines 864 and 1007 (flanking the LXCXE motif). CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, and concurrent phosphorylation of both leads to their dissociation, releasing the mSIN3·HDAC complex. RBP1 phosphorylation is increased during G1-to-S phase progression with concurrent decreased pRb association.\",\n      \"method\": \"In vitro kinase assay, mutagenesis of phosphorylation sites, co-immunoprecipitation in MCF-7 cells at different cell cycle phases, cell synchronization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus in vivo cell cycle validation\",\n      \"pmids\": [\"21148318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBP1 (ARID4A) acts as a coactivator of Runx2 transcriptional activity and promotes osteoblastic differentiation; knockdown of RBP1 in primary calvarial osteoblasts delays mineralization and reduces expression of Runx2, osterix, BMP2, alkaline phosphatase, osteocalcin, and bone sialoprotein. RBP1 regulates Runx2 expression through the proximal P2 Runx2 promoter.\",\n      \"method\": \"shRNA lentiviral knockdown, osteoblastic differentiation assays, Alizarin Red staining, transient transfection coactivation assays with Runx2 reporters, QPCR\",\n      \"journal\": \"BMC musculoskeletal disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined phenotype plus reporter assay, single lab\",\n      \"pmids\": [\"20509905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ARID4A and ARID4B physically interact with each other. Combined deficiency of Arid4a and Arid4b haploinsufficiency in mice causes spermatogenic arrest, impaired blood-testis barrier, and seminal vesicle agenesis/hypodysplasia—phenotypes recapitulating Sertoli cell-specific AR and RB knockouts. ARID4A and ARID4B function as transcriptional coactivators for AR and RB, and their AR- and RB-responsive target genes are dysregulated in the mutant testes.\",\n      \"method\": \"Mouse knockout/haploinsufficiency, co-immunoprecipitation (ARID4A-ARID4B interaction), histology, barrier permeability assay, RT-PCR of AR/RB target genes, transactivation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for physical interaction, mouse KO with defined phenotype, genetic epistasis with AR/RB pathways\",\n      \"pmids\": [\"23487765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARID4A and ARID4B are both direct target genes of miR-30d; their mRNA expression is negatively correlated with miR-30d in prostate cancer tissues, and knockout of ARID4A promotes prostate cancer cell proliferation, migration and invasion in vitro, establishing ARID4A as a tumor suppressor in prostate cancer.\",\n      \"method\": \"Luciferase reporter assay (miR-30d target validation), CRISPR/siRNA knockout, proliferation/migration/invasion assays, Pearson correlation in patient samples\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function phenotype with miRNA target validation, single lab\",\n      \"pmids\": [\"29797600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The crystal/NMR structure of the tandem PWWP-ARID domain of RBBP1 (ARID4A) reveals that the ARID domain binds DNA without GC- or AT-rich preference. An acidic loop L12 within the ARID domain acts as a DNA mimic and inhibits DNA binding by occupying the DNA-binding surface; L12 also binds the Tudor and chromobarrel domains and the histone H2A-H2B heterodimer. Loop L12 and DNA cooperatively enhance chromobarrel binding to H3K4me3 and H4K20me3, indicating multi-domain chromatin recognition.\",\n      \"method\": \"Solution NMR structure determination, NMR titration, ITC binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional validation by NMR titration and ITC\",\n      \"pmids\": [\"34506790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel heterozygous missense variant ARID4A p.His411Asp associated with schizophrenia was found to alter the conformation of the PWWP-ARID supramodule (crystal structure at 2.05 Å), weaken dsDNA-binding activity, reduce G0/G1 cell cycle arrest, and promote proliferation of HEK293T cells, establishing that ARID4A ARID domain DNA-binding is required for G1 phase cell cycle control.\",\n      \"method\": \"Crystal structure determination (2.05 Å), dsDNA binding assays, cell cycle analysis by flow cytometry, cell proliferation assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro binding and cell cycle functional validation\",\n      \"pmids\": [\"35365808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARID4A functions as an RNA-binding protein that stabilizes metastasis-suppressing mRNAs (MTSS1, TIMP2, Rb1, PTEN) by binding a conserved structural RNA element in their 3'UTRs. The ARID domain of ARID4A is required for mRNA stabilization and metastasis inhibition; Arid4a suppresses breast tumor metastasis in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RIP-ChIP, EMSA, mRNA stability assay, luciferase reporter assay, gain/loss-of-function in vitro and in vivo xenograft\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and EMSA establish direct RNA binding, functional domain mutagenesis, in vivo validation; single lab\",\n      \"pmids\": [\"40066676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the chromo barrel domain of RBBP1 (ARID4A) was determined. Structural analysis indicated that the chromo barrel domain can recognize histone H4K20me3 similarly to other chromo barrel domains, but ITC assays showed DNA alone does not significantly enhance histone binding by the isolated chromo barrel domain, suggesting DNA-mediated enhancement requires additional domains.\",\n      \"method\": \"X-ray crystallography, ITC binding assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus ITC; single lab, limited functional follow-up\",\n      \"pmids\": [\"29408527\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARID4A (RBBP1) is a multidomain nuclear protein that acts as a transcriptional corepressor by bridging pRB/p130/p107 pocket proteins to the mSIN3-SAP30-HDAC complex via its LXCXE motif and two repression domains (HDAC-dependent R2 and SUMOylation-dependent/HDAC-independent R1), while also functioning as an RNA-binding protein that stabilizes tumor-suppressive mRNAs through their 3'UTRs; it regulates epigenetic marks (H3K9me3, H4K20me3, DNA methylation) at imprinted loci, is phosphorylated by CDK2 to trigger dissociation from pRB during S-phase entry, and serves as a transcriptional coactivator for AR and Runx2, with structural studies revealing that its PWWP-ARID supramodule engages chromatin through DNA binding modulated by an intramolecular acidic loop mimic.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about canonical ARID4A (RBP1/RBBP1 - retinoblastoma binding protein 1, the human tumor suppressor):\n- KEEP: [1], [2], [4], [9], [10], [11], [12], [18], [29], [33], [43], [47], [48], [51], [54], [57 (ARID4A mentioned as HERC2 interactor)], [35], [41]\n- KEEP from gene2pubmed: [13 (Defeo-Jones 1991)], [14 (SIRT1/RBP1)=paper[14 in main]], [19 (mSIN3A complex)], [30 (BRMS1-ARID4A)]\n\nPapers about ALIAS COLLISIONS (different RBP1 genes):\n- EXCLUDE [5],[6],[8],[20],[25],[28],[32],[55],[58] - Drosophila SR splicing factor RBP1 (SRSF1 ortholog)\n- EXCLUDE [5],[36],[40] - nematode Gp-RBP-1\n- EXCLUDE [7] - ARID4A mutation frequency only (no mechanism)\n- EXCLUDE [13 main] - yeast RBP1 (rDNA binding)\n- EXCLUDE [15] - RBP1 = cellular retinol binding protein\n- EXCLUDE [16] - PAI-RBP1 (SERBP1)\n- EXCLUDE [17] - RBP4/RBP1 chromosomal mapping (retinol binding proteins)\n- EXCLUDE [19 main] - retinol-binding protein in OSCC\n- EXCLUDE [21] - RBP1 = retinol binding protein in ovarian cancer\n- EXCLUDE [22] - Plasmodium RBP-1\n- EXCLUDE [23] - RBP1/RBP2 = retinol binding proteins / BPES mapping\n- EXCLUDE [24] - S. cerevisiae RNA-binding RBP1\n- EXCLUDE [26] - Candida RBP1 (rapamycin-binding)\n- EXCLUDE [27] - Cyanobacterium Rbp1\n- EXCLUDE [30 main] - RBP1 as Runx2 coactivator in osteoblasts (this is about retinoblastoma binding protein 1 = ARID4A context but describes osteoblast function)\n- EXCLUDE [31] - PAI-RBP1 (SERBP1)\n- EXCLUDE [34] - RBBP1 estrogen regulation in osteoblasts - KEEP (this IS ARID4A/RBBP1)\n- EXCLUDE [37] - yeast FKB1/FPR1/RBP1 (FKBP)\n- EXCLUDE [38],[50] - barley HvGR-RBP1\n- EXCLUDE [39] - yeast CTBP1/RBP1\n- EXCLUDE [42] - Bombyx mori Bmrbp1 (SR splicing factor)\n- EXCLUDE [44] - RBP-1 CTL peptides (breast cancer, but this IS about ARID4A/RBBP1 - KEEP)\n- EXCLUDE [45] - RBP1 = retinol binding protein (coronary artery disease)\n- EXCLUDE [46] - RBP1 = cellular retinol binding protein (visual cycle)\n- EXCLUDE [52] - circSPINT2/RBP1 axis - RBP1 here is retinol binding protein\n- EXCLUDE [53] - cyanobacterium rbp1\n- EXCLUDE [56] - rat Rbp1 = cellular retinol binding protein\n- EXCLUDE [59] - Rpb1 = RNA polymerase II subunit (yeast)\n- EXCLUDE [60] - cyanobacterium Rbp3\n\nFor gene2pubmed:\n- KEEP: [13 Defeo-Jones 1991 PMID:1857421], [14 SAP30 PMID:9651585 - relevant as ARID4A is in this complex], [19 Fleischer 2003 PMID:12724404 - mSIN3A complex with RBP1/SAP180], [30 BRMS1-ARID4A PMID:18211900]\n- EXCLUDE large-scale proteomics/interactome papers that don't specifically characterize ARID4A mechanism\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"ARID4A (RBP1) was identified as a cellular protein that directly binds to the retinoblastoma gene product pRb through a conserved LXCXE-like motif. In vitro binding assays showed RBP1 specifically binds pRb, and this interaction is disrupted by HPV-16 E7 protein and by mutations in the putative pRb-binding segment of RBP1.\",\n      \"method\": \"cDNA expression library screen with recombinant pRb, in vitro binding assay, site-directed mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original discovery with in vitro reconstitution, mutagenesis, and competitive inhibition\",\n      \"pmids\": [\"1857421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"RBP1 (ARID4A) is a large (~200 kDa) nuclear phosphoprotein ubiquitously expressed, and forms stable complexes with pRb in vivo that are dissociated by purified HPV E7 protein. The protein undergoes alternative splicing in an internal exon containing potential casein kinase II and p34cdc2 phosphorylation sites, generating a family of RB-binding isoforms.\",\n      \"method\": \"cDNA cloning, immunoblot, co-immunoprecipitation, in vivo complex analysis, in vitro RB-binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP in vivo, replicated by two papers (PMID:8414517, PMID:8455946)\",\n      \"pmids\": [\"8414517\", \"8455946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RBP1 (ARID4A) functions as a transcriptional corepressor that recruits both HDAC-dependent and HDAC-independent repression activities to the pRb family pocket. RBP1 contains two repression domains: one (R2) binds all three known HDACs (HDAC1, HDAC2, HDAC3) and represses transcription in an HDAC-dependent manner; the other functions independently of HDACs. Overexpression of RBP1 inhibits E2F-mediated transcription and suppresses cell growth.\",\n      \"method\": \"Transcriptional repression assays, co-immunoprecipitation, HDAC activity assays, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, functional domain mapping with repression assays\",\n      \"pmids\": [\"10490602\", \"10321733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RBP1 (ARID4A) is a component of the mSIN3-SAP30-HDAC complex. SAP30 was identified as a component of a human histone deacetylase complex that includes Sin3, HDAC1/2, and RBP1 as a bridging factor connecting pRb to this repressor complex.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, mass spectrometry identification of complex components\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification and co-IP establishing complex membership\",\n      \"pmids\": [\"9651585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RBP1 (ARID4A) recruits the mSIN3-SAP30-HDAC complex (containing exclusively class I HDACs) to the pRb family pocket via the LXCXE motif. In quiescent normal human cells, the entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with RB family members and E2F4 in discrete nuclear regions corresponding to initial origins of DNA replication. RBP1 accounts for the majority of RB-associated HDAC activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, HDAC activity assays, cell fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (co-IP, imaging, enzymatic assay) in a single rigorous study\",\n      \"pmids\": [\"11283269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BRMS1 (breast cancer metastasis suppressor 1) interacts with ARID4A (RBP1) and at least seven members of the mSIN3 HDAC complex in human breast and melanoma cell lines. BRMS1 co-immunoprecipitates enzymatically active HDAC proteins and exists in large mSIN3 complexes (~1.4–1.9 MDa). ARID4A is thus a component of a SIN3-HDAC chromatin remodeling complex involved in metastasis suppression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, gel filtration, transcriptional repression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus reciprocal co-IP plus enzymatic activity, multiple cell lines\",\n      \"pmids\": [\"14581478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAP180, a protein 40% identical to RBP1/ARID4A, was identified as a novel mSIN3A-associated protein. RBP1 itself is confirmed as a component of the mSIN3A corepressor complex; all SAPs (including RBP1) bind to the HDAC-interaction domain (HID) of mSIN3A, suggesting that the HID functions as an assembly interface for the mSIN3A corepressor complex.\",\n      \"method\": \"Biochemical purification from K562 cells, co-immunoprecipitation, gel filtration, transcriptional repression assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification plus functional repression assays, domain mapping\",\n      \"pmids\": [\"12724404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBP1 (ARID4A) family members exhibit SUMOylation-dependent transcriptional repression. The R1 repression region contains a SUMOylated moiety (R1σ) that represses both basal and activated transcription in a SUMOylation-dependent manner, and an alpha-helical region (R1α) embedded within the ARID domain that represses only basal transcription. Overexpression of RBP1 causes profound inhibition of cell proliferation and induces expression of a senescence marker, requiring both R1 and R2 domains.\",\n      \"method\": \"Transcriptional repression assays, SUMOylation analysis, cell proliferation/senescence assays, domain deletion analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, domain mapping with functional validation\",\n      \"pmids\": [\"16479010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rbbp1/Arid4a and Rbbp1l1/Arid4b regulate genomic imprinting at the PWS/AS domain. RBBP1/ARID4A physically interacts with RBBP1L1/ARID4B and with the Snrpn promoter. Combined homozygous deficiency for Arid4a and heterozygous deficiency for Arid4b altered epigenetic modifications at the PWS-IC, reducing trimethylation of histone H4K20 and H3K9 and reducing DNA methylation. Mutations in Arid4a, Arid4b, or Rb suppressed an AS imprinting defect.\",\n      \"method\": \"Gene trap mutagenesis, mouse knockout, chromatin immunoprecipitation, western blot, immunofluorescence, genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mouse knockout with multiple epigenetic readouts, genetic epistasis with Rb pathway\",\n      \"pmids\": [\"17043311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIRT1 negatively regulates HDAC1-dependent transcriptional repression by RBP1 (ARID4A). The HDAC-dependent R2 domain of RBP1 is necessary and sufficient for interaction with SIRT1. The ING1b and ING2 subunits of the mSIN3A/HDAC1 complex recruit SIRT1 to the R2 domain. SIRT1 activity inhibits R2-mediated mSIN3A/HDAC1 transcriptional repression, establishing a class III HDAC regulatory mechanism over class I HDAC activity.\",\n      \"method\": \"In vitro and in vivo binding assays, transcriptional repression assays with sirtuin activator (resveratrol) and inhibitor (sirtinol), domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays plus pharmacological perturbation in functional repression assays\",\n      \"pmids\": [\"18193082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Arid4a functions as a leukemia suppressor gene. Arid4a-deficient mice develop ineffective hematopoiesis, transition to CMML-like myelodysplastic/myeloproliferative disorder, and then AML. Arid4a deficiency causes increased trimethylation of H3K4, H3K9, and H4K20 in bone marrow. Hox gene expression (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3 are reduced in Arid4a-deficient bone marrow.\",\n      \"method\": \"Mouse knockout, complete blood counts, flow cytometry, histology, RT-PCR, western blot, immunofluorescence\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined hematopoietic phenotype and molecular mechanism (histone marks, target genes)\",\n      \"pmids\": [\"18728284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BRMS1 interaction with ARID4A is required for specific aspects of SIN3-HDAC complex function. BRMS1(L174D) disrupts direct ARID4A interaction in yeast two-hybrid but retains indirect association by co-IP; BRMS1(ΔCC1) prevents co-IP association. These mutations alter complex composition, impair basal transcription repression, and differentially regulate osteopontin, but both mutants still suppress metastasis by downregulating EGFR.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, gene expression analysis, xenograft metastasis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but focused on BRMS1 mutants; ARID4A role inferred\",\n      \"pmids\": [\"18211900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDK2 phosphorylates RBP1 (ARID4A) on serines 864 and 1007 (flanking the LXCXE motif). CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, and concurrent phosphorylation of both proteins causes their dissociation, releasing the mSIN3-HDAC transcriptional repressor complex from pRb. RBP1 phosphorylation increases during G1-to-S phase progression in MCF-7 cells.\",\n      \"method\": \"In vitro kinase assay, in vitro binding assay, cell cycle synchronization, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus cell-cycle-correlated co-IP\",\n      \"pmids\": [\"21148318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ARID4A and ARID4B physically interact with each other and are required for male fertility. In Sertoli cells, ARID4A and ARID4B function as transcriptional coactivators for androgen receptor (AR) and RB, regulating AR- and RB-responsive genes. Their combined deficiency causes spermatogenic arrest, impaired blood-testis barrier integrity, hypogonadism, and seminal vesicle agenesis, phenocopying Sertoli cell-specific AR and RB knockouts.\",\n      \"method\": \"Mouse knockout, co-immunoprecipitation (ARID4A-ARID4B interaction), RT-PCR analysis of downstream targets, histology, barrier permeability assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mouse KO with specific phenotypic readouts, co-IP for physical interaction, genetic epistasis with AR and RB pathways\",\n      \"pmids\": [\"23487765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARID4A and ARID4B are direct target genes of microRNA-30d in prostate cancer. Knockout of ARID4A and ARID4B promotes PCa cell proliferation, migration, and invasion in vitro, indicating a tumor suppressor function.\",\n      \"method\": \"Luciferase reporter assay (miR-30d targeting), CRISPR/siRNA knockdown, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with cellular phenotype but no pathway placement beyond miR-30d targeting\",\n      \"pmids\": [\"29797600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The chromo barrel domain of RBBP1 (ARID4A) was crystallized. Structural analysis indicates it could interact with histone H4K20me3 similarly to other chromo barrel domains, but ITC assays showed DNA does not significantly enhance H4K20me3 binding by the isolated chromo barrel domain, and the domain lacks a typical DNA-binding surface.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry (ITC)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method (crystal structure + ITC) but only the isolated domain studied; functional consequences not established\",\n      \"pmids\": [\"29408527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The tandem PWWP-ARID domain structure of RBBP1 (ARID4A) was determined by NMR. The ARID domain binds DNA without AT-rich or GC-rich sequence preference. A long flexible acidic loop L12 within the ARID domain acts as a DNA mimic, binding to the ARID DNA-binding region and inhibiting DNA binding in cis. Loop L12 also binds weakly to Tudor and chromo barrel domains of RBBP1, and more strongly to histone H2A-H2B. Both L12 and DNA enhance the chromo barrel domain's binding to H3K4me3 and H4K20me3, supporting a model of coordinated chromatin recognition.\",\n      \"method\": \"NMR structure determination, NMR titration, isothermal titration calorimetry, domain deletion analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus multiple binding assays with functional validation of loop L12 as DNA mimic\",\n      \"pmids\": [\"34506790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A missense variant ARID4A p.His411Asp was identified in schizophrenia patients. The crystal structure of the PWWP-ARID tandem domain at 2.05 Å resolution revealed that PWWP and ARID form a structural supramodule. The p.His411Asp mutant adopts a less compact conformation, exhibits weaker dsDNA-binding, decreases G0-G1 cell cycle arrest, and promotes HEK293T cell proliferation, linking ARID4A's DNA-binding function to G1 cell cycle arrest.\",\n      \"method\": \"Whole-exome sequencing, X-ray crystallography (2.05 Å), DNA-binding assays, cell cycle analysis, cell proliferation assay, mutagenesis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis, DNA-binding assays, and cell cycle functional readout\",\n      \"pmids\": [\"35365808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARID4A (Arid4a) functions as an RNA-binding protein that stabilizes transcripts of metastasis-suppressing genes including MTSS1, TIMP2, Rb1, and PTEN by binding to a conserved structural RNA element in their 3'UTRs. The ARID domain of Arid4a is required for this mRNA stabilization activity. Loss of Arid4a promotes breast tumor metastasis in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RIP-ChIP, EMSA, luciferase assay, mRNA stability assay, in vitro/in vivo metastasis experiments\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus EMSA plus mRNA stability assays establish direct RNA binding; single lab, novel finding\",\n      \"pmids\": [\"40066676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HERC2 binds to ARID4A through a 'DxDKDxD' motif recognized by the RLD2 domain of HERC2, identifying ARID4A as one of a small set of HERC2-interacting proteins relevant to brain development.\",\n      \"method\": \"Quantitative binding assays, X-ray crystallography, sequence conservation analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 method but preprint, single study, ARID4A is one of many identified interactors without specific functional follow-up\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A survey of DNA-binding properties across the ARID family showed that ARID4A's ARID domain, like most ARID subfamily members, binds DNA without obvious sequence preference (not restricted to AT-rich sequences). DNA-binding affinity varies between subfamilies, and site-specific mutagenesis did not support specific amino acid determinants in Loop 2 or Helix 5 as primary drivers of sequence specificity.\",\n      \"method\": \"In vitro DNA-binding assays, site-specific mutagenesis across ARID family\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic in vitro binding assays across family members with mutagenesis\",\n      \"pmids\": [\"15640446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARID4A (RBBP1) is a large nuclear phosphoprotein that binds pRb family members via an LXCXE motif and serves as a bridging molecule recruiting the mSIN3-SAP30-HDAC corepressor complex to repress E2F-dependent transcription; its two repression domains (R1, SUMOylation-dependent; R2, HDAC-dependent via SAP30) mediate growth arrest and cellular senescence, CDK2 phosphorylation of RBP1 at S864/S1007 dissociates it from pRb to relieve repression at G1-S, SIRT1 recruited by ING proteins negatively regulates its HDAC-dependent repression, and ARID4A additionally functions as an RNA-binding protein stabilizing metastasis-suppressor transcripts through 3'UTR elements, while its tandem PWWP-ARID supramodule engages chromatin through DNA-independent and -dependent histone modification recognition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARID4A is a multidomain nuclear corepressor that bridges retinoblastoma family pocket proteins (pRB, p130, p107) to the mSIN3–SAP30–HDAC1/2/3 complex via its LXCXE motif, thereby repressing E2F-dependent transcription and enforcing G1 cell cycle arrest [PMID:8414517, PMID:10490602, PMID:11283269, PMID:10321733]. It possesses two mechanistically distinct repression domains—an HDAC-dependent R2 domain that also recruits SIRT1 (which antagonizes R2-mediated repression) and a SUMOylation-dependent, HDAC-independent R1 domain—and CDK2-mediated phosphorylation of ARID4A during S-phase entry triggers its dissociation from pRB, releasing the repressor complex [PMID:16479010, PMID:18193082, PMID:21148318]. Beyond corepression, ARID4A functions as a coactivator for the androgen receptor and Runx2, regulates epigenetic marks (H3K9me3, H4K20me3, DNA methylation) at imprinted loci when acting with ARID4B and RB, and binds RNA through its ARID domain to stabilize tumor-suppressive mRNAs via their 3′UTRs, suppressing metastasis [PMID:23487765, PMID:20509905, PMID:17043311, PMID:40066676]. Structural studies show the PWWP–ARID supramodule engages DNA without sequence preference, with an intramolecular acidic loop (L12) acting as a DNA mimic that modulates DNA binding and cooperatively enhances chromobarrel-domain recognition of methylated histones, and a disease-associated missense variant that weakens DNA binding impairs G1 arrest [PMID:34506790, PMID:35365808].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying ARID4A as a direct pRB-binding protein established it as a potential effector of retinoblastoma-mediated growth control, resolving the question of whether pRB engages large nuclear phosphoproteins through its pocket domain.\",\n      \"evidence\": \"cDNA cloning, co-immunoprecipitation from cell lysates, and HPV E7 competition assay demonstrating LXCXE-type binding\",\n      \"pmids\": [\"8414517\", \"8455946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nature of transcriptional effect of RBP1 on pRB targets was unknown\", \"No enzymatic or chromatin-modifying activity attributed to ARID4A itself\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that ARID4A contains dual repression domains—one HDAC-dependent (R2) and one HDAC-independent—and that its overexpression suppresses E2F activity and cell growth established it as a bona fide corepressor linking pRB to chromatin modification.\",\n      \"evidence\": \"Domain-deletion mutagenesis, HDAC binding assays, E2F reporter assays, and cell growth suppression assays in transfected cells\",\n      \"pmids\": [\"10490602\", \"10321733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous HDAC-containing complex was not resolved\", \"Mechanism of HDAC-independent repression domain was undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that ARID4A forms a stable complex with mSIN3–SAP30–HDAC that colocalizes with pRB/E2F4 at replication origins identified the precise repressor complex architecture and placed ARID4A at the interface between pocket proteins and chromatin remodelers.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, immunofluorescence colocalization, and nuclear fractionation in quiescent cells\",\n      \"pmids\": [\"11283269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of ARID4A to replication origin regulation was not tested\", \"Stoichiometry of ARID4A within the complex was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of BRMS1 as an ARID4A partner within large (~1.4–1.9 MDa) mSIN3 complexes expanded the complex composition and linked ARID4A to metastasis suppression pathways.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation with enzymatic HDAC activity assays\",\n      \"pmids\": [\"14581478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of BRMS1–ARID4A interaction on target gene repression was not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that the R1 domain's repression requires SUMOylation (R1σ subdomain) and that both R1 and R2 are needed for growth-arrest/senescence phenotypes resolved the mechanistic basis of HDAC-independent repression and established a dual-domain requirement for full biological activity.\",\n      \"evidence\": \"Domain-deletion mutagenesis, transcriptional repression assays, cell proliferation and senescence marker analysis\",\n      \"pmids\": [\"16479010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase responsible for R1σ modification was not identified\", \"Genome-wide targets of R1-mediated repression were not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mouse genetic studies revealed that ARID4A, together with ARID4B and RB, maintains repressive epigenetic marks (H3K9me3, H4K20me3, DNA methylation) at the imprinted PWS-IC locus and that their loss suppresses Angelman syndrome imprinting defects, establishing ARID4A as an epigenetic regulator of genomic imprinting.\",\n      \"evidence\": \"Gene trap mutagenesis and mouse knockout with ChIP, bisulfite sequencing, and genetic epistasis with AS-IC mutation\",\n      \"pmids\": [\"17043311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4A directly recognizes the PWS-IC or is recruited indirectly was not resolved\", \"Mechanism by which ARID4A controls DNA methylation was unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that Arid4a knockout mice develop myelodysplastic/myeloproliferative disease and AML with altered histone methylation and Hox gene dysregulation established ARID4A as a leukemia suppressor, while the finding that SIRT1 antagonizes R2-mediated repression revealed a regulatory layer linking class III and class I HDACs on ARID4A.\",\n      \"evidence\": \"Mouse knockout with blood counts, histology, flow cytometry, and histone modification western blots; binding assays and pharmacological modulation (resveratrol/sirtinol) for SIRT1\",\n      \"pmids\": [\"18728284\", \"18193082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific target genes driving leukemic transformation were not fully identified\", \"In vivo relevance of SIRT1-ARID4A antagonism was not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"CDK2-mediated phosphorylation of ARID4A at S864/S1007 during G1-to-S transition, which triggers dissociation from pRB and release of the mSIN3·HDAC complex, provided the cell cycle switch mechanism that inactivates ARID4A-mediated repression at S-phase entry.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mutagenesis, co-immunoprecipitation across cell cycle phases in synchronized MCF-7 cells\",\n      \"pmids\": [\"21148318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation also affects R1-mediated or SUMOylation-dependent activities was unknown\", \"Phosphatase responsible for dephosphorylation during re-entry into G0/G1 was not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that ARID4A coactivates Runx2 and promotes osteoblast mineralization demonstrated that ARID4A can function as a transcriptional coactivator in addition to its corepressor role, broadening its functional repertoire beyond pRB-E2F.\",\n      \"evidence\": \"shRNA knockdown in primary calvarial osteoblasts, Alizarin Red staining, Runx2 promoter reporter assays, qPCR\",\n      \"pmids\": [\"20509905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of coactivation (direct contact with Runx2 versus indirect) was not determined\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that ARID4A and ARID4B physically interact and function as coactivators for the androgen receptor and RB in testis, with compound-mutant mice recapitulating AR/RB-knockout phenotypes, established ARID4A as a context-dependent coactivator essential for spermatogenesis and male reproductive development.\",\n      \"evidence\": \"Co-immunoprecipitation, compound-mutant mouse analysis, histology, barrier permeability, RT-PCR of AR/RB targets, transactivation assays\",\n      \"pmids\": [\"23487765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AR-binding surface on ARID4A was not mapped\", \"Mechanism by which the same protein switches between corepressor and coactivator roles was unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural determination of the chromo barrel domain and tandem PWWP-ARID module revealed that ARID4A reads methylated histones (H4K20me3, H3K4me3) and binds DNA without sequence preference, with an acidic loop L12 acting as a DNA mimic that auto-inhibits DNA binding and cooperatively enhances histone mark recognition.\",\n      \"evidence\": \"X-ray crystallography, solution NMR, ITC binding assays, NMR titration\",\n      \"pmids\": [\"29408527\", \"34506790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of L12 auto-inhibition was not tested\", \"Whether PWWP domain reads specific histone marks was unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A schizophrenia-associated ARID4A missense variant (H411D) that alters the PWWP-ARID supramodule conformation, weakens DNA binding, and impairs G1 arrest provided direct evidence that ARID domain DNA-binding integrity is required for cell cycle control, and linked ARID4A dysfunction to neuropsychiatric disease.\",\n      \"evidence\": \"Crystal structure at 2.05 Å, dsDNA binding assays, flow cytometry cell cycle analysis, cell proliferation assay in HEK293T cells\",\n      \"pmids\": [\"35365808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal-specific consequences of H411D were not studied\", \"Whether this variant is causative for schizophrenia or a risk factor was not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing that ARID4A functions as an RNA-binding protein that stabilizes tumor-suppressive mRNAs (MTSS1, TIMP2, Rb1, PTEN) through a conserved 3′UTR structural element added a post-transcriptional mechanism to its tumor/metastasis suppressor activities, distinct from its transcriptional corepressor function.\",\n      \"evidence\": \"RNA immunoprecipitation, RIP-ChIP, EMSA, mRNA stability assays, luciferase reporters, gain/loss-of-function in vitro and in vivo xenograft models\",\n      \"pmids\": [\"40066676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding specificity determinants within the ARID domain were not structurally mapped\", \"Not independently replicated\", \"Overlap between RNA-binding and DNA-binding surfaces of ARID domain raises unresolved competition questions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARID4A switches between corepressor (E2F targets) and coactivator (AR, Runx2) modes, the structural basis for its RNA versus DNA binding selectivity, and the genome-wide catalog of its direct chromatin targets remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN map of ARID4A occupancy in any cell type\", \"Structural mechanism of coactivator versus corepressor switching is unknown\", \"Competition between RNA and DNA binding by the ARID domain has not been dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 6, 12]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 10, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 6, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 8, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"mSIN3A–SAP30–HDAC complex\",\n      \"pRB–E2F repressor complex\"\n    ],\n    \"partners\": [\n      \"RB1\",\n      \"ARID4B\",\n      \"HDAC1\",\n      \"HDAC2\",\n      \"SIN3A\",\n      \"SAP30\",\n      \"BRMS1\",\n      \"SIRT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ARID4A is a nuclear transcriptional corepressor that bridges the retinoblastoma protein (pRb) to the mSIN3–SAP30–HDAC chromatin-remodeling complex, thereby repressing E2F-dependent transcription and enforcing G1 cell-cycle arrest and cellular senescence [PMID:1857421, PMID:9651585, PMID:11283269, PMID:16479010]. It harbors two repression domains—R1, which operates through SUMOylation-dependent mechanisms, and R2, which recruits class I HDACs via SAP30—and CDK2-mediated phosphorylation at S864/S1007 dissociates ARID4A from pRb at the G1–S transition, relieving repression [PMID:16479010, PMID:21148318]. Beyond transcriptional repression, ARID4A regulates genomic imprinting at the PWS/AS locus through modulation of histone methylation and DNA methylation, acts as a leukemia and metastasis suppressor whose loss causes myeloid malignancy in mice, and functions as an RNA-binding protein that stabilizes metastasis-suppressor transcripts via 3′UTR elements [PMID:17043311, PMID:18728284, PMID:40066676]. Its tandem PWWP–ARID supramodule binds DNA without sequence preference and coordinately engages modified histones (H3K4me3, H4K20me3), with an internal acidic loop acting as a DNA mimic to regulate chromatin association [PMID:34506790, PMID:35365808].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that ARID4A is a direct pRb-binding protein revealed a new class of pocket-protein interactor and raised the question of what effector function ARID4A brings to the Rb pathway.\",\n      \"evidence\": \"cDNA expression library screen with recombinant pRb, in vitro binding with mutagenesis and E7 competition\",\n      \"pmids\": [\"1857421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No indication of ARID4A's transcriptional or enzymatic function\", \"Binding site on pRb not precisely mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of ARID4A as a subunit of the mSIN3–SAP30–HDAC complex answered how pRb achieves HDAC-dependent gene silencing—ARID4A acts as the physical bridge recruiting this corepressor complex to the pocket domain.\",\n      \"evidence\": \"Biochemical purification of the mSIN3A complex from human cells, co-immunoprecipitation, mass spectrometry\",\n      \"pmids\": [\"9651585\", \"10490602\", \"10321733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the ARID4A–mSIN3–HDAC holocomplex unresolved\", \"Relative contribution of R1 vs R2 repression domains to growth suppression not yet dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that the entire ARID4A–mSIN3–HDAC complex colocalizes with pRb/E2F4 at replication origins in quiescent cells placed ARID4A at a defined nuclear site and implied a role in DNA replication licensing control.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, HDAC activity assays, and cell fractionation in quiescent human fibroblasts\",\n      \"pmids\": [\"11283269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role at replication origins not tested by functional assays\", \"Whether ARID4A is required for replication origin silencing remains untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of BRMS1 and SAP180 (ARID4B) as ARID4A interaction partners expanded the mSIN3 complex membership and connected ARID4A to metastasis suppression and paralog redundancy.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, gel filtration in breast cancer and melanoma lines; biochemical purification from K562 cells\",\n      \"pmids\": [\"14581478\", \"12724404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional distinction between ARID4A and ARID4B within the complex unclear\", \"Whether BRMS1–ARID4A interaction is essential for metastasis suppression not resolved until later mutant studies\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissection of ARID4A's two repression domains revealed that R1 acts through SUMOylation and R2 through HDAC recruitment, and both are required for growth arrest and senescence—answering how a single protein enforces dual modes of transcriptional silencing.\",\n      \"evidence\": \"SUMOylation assays, transcriptional repression assays, domain deletions, cell proliferation and senescence marker analysis\",\n      \"pmids\": [\"16479010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of SUMO E3 ligase targeting R1 unknown\", \"Endogenous genomic targets repressed by R1 vs R2 not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mouse genetic studies showed ARID4A cooperates with ARID4B and Rb to maintain imprinting at the PWS/AS locus through histone H3K9/H4K20 trimethylation and DNA methylation, extending its role from transcriptional repression to epigenetic imprint maintenance.\",\n      \"evidence\": \"Gene-trap mutagenesis, compound Arid4a/Arid4b knockout mice, ChIP for histone marks, genetic suppression of AS imprinting defect\",\n      \"pmids\": [\"17043311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which histone methyltransferase is recruited by ARID4A not identified\", \"Whether imprinting role is direct or mediated through global Rb pathway not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two key regulatory inputs were identified: CDK2 phosphorylation at S864/S1007 dissociates ARID4A from pRb to relieve repression at G1–S, while SIRT1 recruited by ING proteins antagonizes R2-mediated HDAC1 repression, establishing how cell cycle and sirtuin signaling converge on the ARID4A–Rb axis.\",\n      \"evidence\": \"In vitro kinase assay with mutagenesis, cell-cycle-synchronized co-IP (CDK2); binding assays with sirtuin activator/inhibitor (SIRT1)\",\n      \"pmids\": [\"21148318\", \"18193082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK2 phosphorylation occurs in vivo on endogenous ARID4A not confirmed by phospho-specific antibody\", \"How SIRT1-mediated deacetylation specifically inactivates R2 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Arid4a knockout mice developed myelodysplastic disorder progressing to AML with altered H3K4/H3K9/H4K20 trimethylation and deregulated Hox gene expression, establishing ARID4A as a bona fide leukemia suppressor.\",\n      \"evidence\": \"Arid4a-null mice, complete blood counts, flow cytometry, histology, RT-PCR, histone mark western blots\",\n      \"pmids\": [\"18728284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether leukemia suppression is Rb-dependent or reflects Rb-independent ARID4A functions not determined\", \"Direct target genes driving leukemogenesis upon ARID4A loss not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that ARID4A and ARID4B function as transcriptional coactivators for the androgen receptor in Sertoli cells, with their loss phenocopying AR and Rb knockouts, revealed a tissue-specific coactivator role beyond the canonical corepressor paradigm.\",\n      \"evidence\": \"Sertoli cell-specific compound knockout mice, co-IP for ARID4A–ARID4B interaction, RT-PCR of AR/Rb target genes, histology and barrier assays\",\n      \"pmids\": [\"23487765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ARID4A switches from corepressor to coactivator not identified\", \"Whether direct AR interaction occurs or is mediated by Rb not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural determination of the PWWP–ARID supramodule by NMR revealed that an internal acidic loop (L12) acts as a DNA mimic, auto-inhibiting DNA binding and allosterically enhancing chromo barrel recognition of H3K4me3 and H4K20me3, providing a mechanistic basis for coordinated chromatin engagement.\",\n      \"evidence\": \"NMR structure, NMR titration, ITC, domain deletion analysis\",\n      \"pmids\": [\"34506790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether L12 autoinhibition is relieved by post-translational modifications in vivo unknown\", \"Which genomic loci require loop L12-mediated regulation not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A schizophrenia-associated missense variant (p.His411Asp) in the PWWP–ARID supramodule was shown to destabilize the domain, reduce DNA binding, and impair G1 arrest, linking ARID4A chromatin engagement to a neuropsychiatric phenotype.\",\n      \"evidence\": \"Crystal structure at 2.05 Å, DNA-binding assays, cell cycle and proliferation assays on wild-type vs mutant, whole-exome sequencing of schizophrenia cohort\",\n      \"pmids\": [\"35365808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causality of the variant in schizophrenia not established by family segregation or animal model\", \"Whether the structural defect affects histone-mark recognition in addition to DNA binding not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that ARID4A is an RNA-binding protein that stabilizes metastasis-suppressor transcripts (MTSS1, TIMP2, Rb1, PTEN) via conserved 3′UTR elements expanded its functional repertoire beyond chromatin-directed transcriptional regulation to post-transcriptional mRNA stability control.\",\n      \"evidence\": \"RIP, RIP-ChIP, EMSA, luciferase 3′UTR reporters, mRNA stability assays, in vivo breast cancer metastasis model\",\n      \"pmids\": [\"40066676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding specificity determinants within the ARID domain not structurally resolved\", \"Whether RNA binding is independent of or competitive with DNA/chromatin binding untested\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for ARID4A's switch between corepressor and coactivator functions, the identity of SUMO E3 ligases and histone methyltransferases it recruits, the full repertoire of RNA targets and whether RNA and DNA binding are mutually exclusive, and whether ARID4A's roles in leukemia suppression and imprinting are Rb-dependent or autonomous.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted holocomplex structure available\", \"Genome-wide direct target map by ChIP-seq in a physiological context not reported\", \"In vivo validation of RNA-binding function in development/disease models lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 4, 7, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [16, 17, 20]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 8, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 7, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 14]}\n    ],\n    \"complexes\": [\n      \"mSIN3A–HDAC corepressor complex\",\n      \"pRb–E2F repressor complex\"\n    ],\n    \"partners\": [\n      \"RB1\",\n      \"SIN3A\",\n      \"SAP30\",\n      \"HDAC1\",\n      \"HDAC2\",\n      \"ARID4B\",\n      \"BRMS1\",\n      \"SIRT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}