{"gene":"RSF1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2002,"finding":"HBXAP (RSF1) physically interacts with hepatitis B virus X protein (pX) in vitro and in vivo via the HBXAP region containing the PHD finger domain. This interaction coactivates HBV transcription and NF-κB-mediated transcription.","method":"Co-immunoprecipitation, in vitro binding assay, transcription reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding with functional transcription assay, single lab","pmids":["11788598"],"is_preprint":false},{"year":2002,"finding":"HBXAP (RSF1) possesses intrinsic transcriptional repression activity when recruited to DNA via GAL4; the PHD finger domain alone is sufficient for this repression activity.","method":"GAL4 fusion transcription reporter assay, deletion mutagenesis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — functional reporter assay with domain mutagenesis, single lab","pmids":["11944984"],"is_preprint":false},{"year":2004,"finding":"HBXAP (RSF1) represses NF-κB-mediated gene activation in a dose-dependent manner; HBXAP and NF-κB colocalize at the nuclear matrix with direct physical interaction. A nuclear matrix targeting sequence (aa 688–722, coiled-coil region) and the PHD finger domain are both required for this repression.","method":"Co-immunoprecipitation, immunofluorescence colocalization, reporter gene assay, deletion mutagenesis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, colocalization, and functional reporter with domain mapping, single lab","pmids":["15242768"],"is_preprint":false},{"year":2005,"finding":"RSF1 (HBXAP) overexpression stimulates cell proliferation and confers serum-independent and anchorage-independent growth in non-neoplastic cells; RSF1 knockdown inhibits growth in cells with RSF1 amplification.","method":"Overexpression/knockdown in cell lines, colony formation and growth assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes, single lab","pmids":["16172393"],"is_preprint":false},{"year":2008,"finding":"RSF1 interacts with hSNF2H (SMARCA5) to form a chromatin remodeling complex (RSF complex). Ectopic RSF1 expression upregulates hSNF2H protein levels and translocates hSNF2H to the nucleus where it colocalizes with RSF1. The hSNF2H binding site maps to the Rsf-D4 fragment of RSF1 by coimmunoprecipitation and in vitro competition assay.","method":"Co-immunoprecipitation, in vitro competition assay, immunofluorescence colocalization, deletion mutagenesis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro competition assay with domain mapping plus reciprocal Co-IP and colocalization, replicated across multiple studies","pmids":["18519663"],"is_preprint":false},{"year":2009,"finding":"RSF1 promotes paclitaxel resistance in ovarian cancer cells; this resistance requires formation of the RSF1/hSNF2H complex, as disruption of hSNF2H or the RSF1-hSNF2H interaction restores paclitaxel sensitivity.","method":"siRNA knockdown, ectopic overexpression, drug resistance assays, disruption of complex","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with functional phenotype and complex disruption experiment, single lab","pmids":["19190325"],"is_preprint":false},{"year":2010,"finding":"RSF1 overexpression induces DNA strand breaks, nuclear γH2AX foci, and activates the ATM-CHK2-p53-p21 DNA damage response pathway. Formation of a functional RSF complex with SNF2H is required for RSF1 to trigger this DDR. Chronic RSF1 expression leads to chromosomal aberrations, c-myc amplification, and CDKN2A/B deletion.","method":"Ectopic expression, deletion mutagenesis, gene knockdown, comet assay, γH2AX immunofluorescence, chromosomal analysis, TP53 knockout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (comet assay, γH2AX, pathway analysis, genetic epistasis with TP53 KO and ATM inhibitor), single lab with rigorous controls","pmids":["20923775"],"is_preprint":false},{"year":2013,"finding":"RSF1 interacts with cyclin E1 as identified by co-immunoprecipitation followed by nanoelectrospray mass spectrometry. Ectopic co-expression of RSF1 and cyclin E1 in TP53-mutant cells activates CDK2 and promotes cellular proliferation and tumor formation; the cyclin E1-binding site maps to the first 441 amino acids of RSF1.","method":"Co-immunoprecipitation, nanoelectrospray mass spectrometry, ectopic expression, domain mapping, CDK2 kinase assay, xenograft","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP/MS identification with domain mapping, functional validation by kinase assay and in vivo tumor formation, single lab with multiple orthogonal methods","pmids":["23378270"],"is_preprint":false},{"year":2013,"finding":"RSF1 accumulates at DNA double-strand break (DSB) sites in an ATM-dependent manner; putative ATM phosphorylation sites (pSQ motifs) on RSF1 are required for its DSB accumulation. RSF1 depletion attenuates DNA damage checkpoint signaling and reduces cell survival after damage. RSF1 promotes homologous recombination repair by recruiting resection factors RPA32 and Rad51.","method":"Laser microirradiation, live-cell imaging, immunofluorescence, siRNA depletion, ATM inhibition, RPA32/Rad51 recruitment assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell localization with functional consequence, domain mutagenesis, single lab","pmids":["24351651"],"is_preprint":false},{"year":2013,"finding":"RSF1 deposits centromere proteins CENP-S and CENP-X at DNA DSB sites to promote NHEJ. CENP-S and CENP-X in turn facilitate assembly of NHEJ factor XRCC4 at damaged chromatin. RSF1 also promotes HR repair independently of CENP-S/CENP-X. SMARCA5 regulates RNF168-dependent ubiquitin response (BRCA1 recruitment) but RSF1 is dispensable for this.","method":"siRNA knockdown, laser microirradiation, immunofluorescence recruitment assay, IR survival assay, epistasis analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple knockdowns, live-cell recruitment assays, independently replicated in part by Pessina 2014 (PMID 24800743)","pmids":["23974106"],"is_preprint":false},{"year":2013,"finding":"HBxAPα/RSF1 mediates interaction between HBx viral protein and hBubR1 at the chromatin fraction during mitosis. RSF1 depletion abolishes the HBx-hBubR1 interaction and impairs HBx targeting to kinetochores. HBx binding to hBubR1 (stabilized by RSF1) reduces hBubR1-Cdc20 binding and increases mitotic aberrations.","method":"Co-immunoprecipitation, siRNA knockdown, deletion mutant analysis, kinetochore immunofluorescence","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional epistasis, single lab","pmids":["23536579"],"is_preprint":false},{"year":2014,"finding":"RSF1 physically interacts with ATM in a manner dependent on DSBs and ATM kinase activity. RSF1 is required for ATM-dependent recruitment of CENP-S/MHF1 and CENP-X/MHF2 to DSBs. These proteins in turn regulate mono-ubiquitination of Fanconi Anaemia proteins FANCD2 and FANCI. RSF1 is required for efficient DSB repair via both end-joining and homology-directed repair but is not required for checkpoint signaling.","method":"Co-immunoprecipitation, siRNA knockdown, laser microirradiation, immunofluorescence recruitment assay, epistasis with HR and NHEJ reporters","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for ATM interaction, multiple recruitment assays, epistasis analysis, independent replication of CENP-S/X loading consistent with PMID 23974106","pmids":["24800743"],"is_preprint":false},{"year":2015,"finding":"RSF1 localizes at mitotic kinetochores and directly binds PLK1. CDK1 phosphorylates RSF1 at Ser1375, which is necessary for PLK1 recruitment to kinetochores. Subsequently PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition. RSF1 depletion causes chromosome misalignment phenotype mimicking PLK1 knockdown; rescued by RSF1 S1375D or S1359D but not S1375A phospho-mutants.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, phosphomutant rescue, in vitro kinase assay (CDK1 and PLK1), live-cell imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus genetic rescue experiments, multiple orthogonal methods in single rigorous study","pmids":["26259146"],"is_preprint":false},{"year":2018,"finding":"RSF1 is required for p53-dependent gene transcription in response to DNA strand breaks. RSF1 deficiency reduces binding of the p53/p300 complex and subsequent H3 acetylation at p53 target gene promoters, causing reduced expression of p53 downstream genes.","method":"Neural-specific Rsf1 knockout mouse, chromatin immunoprecipitation, transcriptome analysis, Western blot, immunofluorescence","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo knockout with chromatin immunoprecipitation and genome-wide transcriptome analysis, multiple orthogonal methods","pmids":["30348983"],"is_preprint":false},{"year":2018,"finding":"RSF1 protein levels are transiently upregulated in response to DNA damage at the post-translational level (without changes in mRNA). SNF2H binding partner stabilizes RSF1 protein; ATM-mediated phosphorylation of RSF1 at three SQ sites (RSF1-3SA mutant) destabilizes the protein. Proper temporal regulation of RSF1 levels by SNF2H and ATM is essential for efficient DSB repair.","method":"Western blot under various DNA damage conditions, siRNA knockdown, phosphomutant overexpression, ATM kinase manipulation, DSB repair assay","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomutant analysis with functional repair assay, single lab, multiple conditions","pmids":["29385673"],"is_preprint":false},{"year":2018,"finding":"RSF1 recruits HDAC1 to centromeres, where HDAC1 counteracts TIP60-mediated acetylation of histone H2A at K118. This deacetylation enables accumulation of H2A phosphorylation at T120 (by Bub1) and Sgo1 deposition at centromeres, which is required for faithful chromosome segregation. Centromeric HDAC1 tethering prevents premature chromatid separation in RSF1 knockout cells.","method":"Co-immunoprecipitation, RSF1 knockout, chromatin immunoprecipitation, immunofluorescence, rescue experiments with HDAC1 centromeric tethering","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic knockout with ChIP, functional rescue, histone modification crosstalk established by multiple orthogonal methods in single rigorous study","pmids":["30242288"],"is_preprint":false},{"year":2021,"finding":"Under DNA damage, RSF1 recruits HDAC1 to DSB sites. The RSF1-HDAC1 complex deacetylates H2A(X) at K118, which is required for H2A ubiquitination at K119 (H2A-K119ub) and subsequent transcriptional repression at DNA lesions. Deacetylation of H2AX-K118 also enables γH2AX propagation and MDC1 recruitment, promoting DNA repair. H2A-K118Q acetylation mimetic suppresses H2A-K119ub and impairs repair.","method":"RSF1 depletion, phospho/acetyl mutant analysis, chromatin immunoprecipitation, immunofluorescence, γH2AX analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic dissection with multiple histone mutants, ChIP, and functional repair readouts in single rigorous study","pmids":["34850117"],"is_preprint":false},{"year":2021,"finding":"RSF1 PLK1-axis at centromeres creates an activating phosphorylation on Aurora B at Thr236 (in the activation loop), which is indispensable for Aurora B activation and subsequent microtubule destabilization in error correction. Under full microtubule-kinetochore attachment, RSF1-PLK1 moves to kinetochores, halts Aurora B activation, and phosphorylates BubR1. Aurora B-mediated phosphorylation of centromeric histone H3 at Ser28 triggers the spatial RSF1-PLK1 movement from centromeres to kinetochores.","method":"In vitro kinase assay, structural modeling, phosphomutant analysis, immunofluorescence, siRNA depletion, live-cell imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with structural modeling and multiple phosphomutant validations, multiple orthogonal methods","pmids":["34635673"],"is_preprint":false},{"year":2021,"finding":"RSF1 requires hSNF2H and CEBP/β to cotransactivate the IL1B promoter, increasing IL-1β mRNA, secretion, and downstream angiogenic capacity in myxofibrosarcoma cells. RSF1-driven angiogenesis is counteracted by IL1B knockdown and IL-1β-neutralizing antibodies.","method":"siRNA knockdown, RT-PCR profiling, chromatin reporter assay, IL-1β ELISA, angiogenesis assay, in vivo xenograft","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter activation with co-factor dependency established, in vitro and in vivo validation, single lab","pmids":["33496909"],"is_preprint":false},{"year":2023,"finding":"RSF1 acts as a reader of histone H2A lysine 119 ubiquitination (H2AK119ub). The UAB domain of RSF1 is required to recognize H2AK119ub nucleosomes; deletion of the UAB domain abolishes the ability of RSF1 to rescue developmental defects in Xenopus rsf1 morphants. Ectopic deposition of H2AK119ub recruits RSF1 to the Smad2 target gene gsc.","method":"Xenopus laevis morpholino knockdown, rescue with deletion mutants, in vivo H2AK119ub deposition using ring1a-smad2 fusion, immunoprecipitation","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion rescue experiments in Xenopus with ectopic deposition validation, single lab","pmids":["37529237"],"is_preprint":false},{"year":2024,"finding":"RSF1 promotes p53-dependent p21 (CDKN1A) gene transcription by facilitating accumulation of p300 acetyltransferase at the enhancer and FACT complex (SSRP1, SPT16) at the promoter of CDKN1A. RSF1 depletion reduces acetylated-K382 p53 levels and decreases p300 and TBP binding along with reduced H3K27ac and H3K4me1 at the CDKN1A locus.","method":"Co-immunoprecipitation (RSF1 with p300), chromatin immunoprecipitation, RSF1 knockout cells, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with KO cells, single lab, multiple chromatin marks analyzed","pmids":["39579530"],"is_preprint":false},{"year":2025,"finding":"KAT8 acetyltransferase acetylates RSF1 at K1050, and this acetylation is associated with heterochromatin loss and cellular senescence during skin aging. FTO depletion reduces KAT8 mRNA stability via m6A-YTHDF2 pathway, leading to reduced KAT8 and downstream RSF1 K1050 acetylation.","method":"RNA-seq, MeRIP-seq, acetylation proteomics, siRNA/inhibitor knockdown, m6A modification assays, Western blot","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific acetylation identified by proteomics with functional pathway validation, single lab","pmids":["40636284"],"is_preprint":false},{"year":2025,"finding":"RSF1 and CENP-S/CENPX are recruited to DSBs with a half-time of ~100 s and removed with a half-time of ~2000 s. Recruitment occurs in G1, S, and G2 phases, with stronger/delayed enrichment in G2. RSF1/CENP-S/CENPX arrive simultaneously after ATM activation and RNF8-RNF168 activity, temporally placing them at the time of nucleosome remodeling during early DSB response.","method":"Live-cell microirradiation, quantitative fluorescence time-course imaging, cell cycle phase analysis","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative live-cell kinetics with cell cycle analysis, single lab","pmids":["40450933"],"is_preprint":false}],"current_model":"RSF1 (HBXAP) is a subunit of the ISWI-family RSF chromatin remodeling complex, where it partners with the ATPase SNF2H/SMARCA5; it functions as a reader of H2AK119ub (via its UAB domain), recruits HDAC1 to centromeres and DSB sites to coordinate histone H2A deacetylation (K118) enabling H2A-K119 ubiquitination and γH2AX propagation, deposits centromere proteins CENP-S/X at DSBs to promote NHEJ via XRCC4, recruits PLK1 to kinetochores through CDK1-mediated Ser1375 phosphorylation to regulate Aurora B activity and faithful chromosome segregation, facilitates p53-dependent transcription by scaffolding p300 and FACT at target gene loci, and when overexpressed drives genomic instability via excessive RSF activity, paclitaxel/cisplatin resistance through NF-κB pathway activation, and IL-1β-mediated angiogenesis through co-activation of the IL1B promoter with CEBP/β."},"narrative":{"mechanistic_narrative":"RSF1 (HBXAP) is the substrate-targeting subunit of the ISWI-family RSF chromatin remodeling complex, coupling nucleosome remodeling to DNA damage repair, mitotic chromosome segregation, and p53-dependent transcription [PMID:18519663, PMID:20923775, PMID:30242288]. It binds the ATPase SNF2H/SMARCA5 through its Rsf-D4 region, an interaction that stabilizes RSF1 protein, redistributes SNF2H to the nucleus, and is obligatory for RSF complex remodeling activity [PMID:18519663, PMID:29385673]. At DNA double-strand breaks RSF1 accumulates in an ATM-dependent manner via phosphorylated SQ motifs, physically engages ATM, and deposits the centromere proteins CENP-S/CENP-X to drive both NHEJ (through XRCC4 assembly) and homology-directed repair, while also recruiting resection factors RPA32 and Rad51 [PMID:24351651, PMID:23974106, PMID:24800743, PMID:40450933]. RSF1 recruits HDAC1 to both centromeres and break sites, where deacetylation of histone H2A(X)-K118 licenses H2A-K119 ubiquitination, γH2AX propagation, and MDC1 recruitment, and at centromeres enables H2A-T120 phosphorylation and Sgo1 loading for accurate chromatid cohesion [PMID:30242288, PMID:34850117]. In mitosis, CDK1-mediated phosphorylation of RSF1 at Ser1375 recruits PLK1 to kinetochores, and the RSF1–PLK1 axis spatially regulates Aurora B activation (via Thr236) for error correction and faithful chromosome segregation [PMID:26259146, PMID:34635673]. RSF1 reads H2AK119ub through its UAB domain, linking it to Polycomb-marked chromatin [PMID:37529237]. RSF1 also scaffolds p53/p300 and the FACT complex at target loci such as CDKN1A to support p53-dependent transcription following DNA damage [PMID:30348983, PMID:39579530]. When overexpressed, RSF1 drives genomic instability, anchorage-independent growth, and chemoresistance, and cooperates with cyclin E1 to activate CDK2 in TP53-mutant cells [PMID:16172393, PMID:19190325, PMID:20923775, PMID:23378270].","teleology":[{"year":2002,"claim":"Established RSF1/HBXAP as a chromatin-associated transcriptional regulator able to coactivate viral and NF-κB transcription and to repress transcription via its PHD finger, framing it as a chromatin-acting protein before its remodeling role was known.","evidence":"Co-IP and in vitro binding with HBV pX plus GAL4 fusion reporter and deletion mutagenesis in cell lines","pmids":["11788598","11944984"],"confidence":"Medium","gaps":["Did not identify the remodeling complex or ATPase partner","Mechanism of transcriptional effect through chromatin not defined"]},{"year":2004,"claim":"Localized RSF1 to the nuclear matrix and mapped distinct domains (coiled-coil targeting sequence and PHD finger) required for NF-κB repression, refining its transcriptional regulatory architecture.","evidence":"Co-IP, immunofluorescence colocalization, reporter assays with deletion mutagenesis","pmids":["15242768"],"confidence":"Medium","gaps":["Direct vs. indirect NF-κB regulation not resolved","Relationship to remodeling activity unknown"]},{"year":2005,"claim":"Demonstrated that RSF1 functions as an oncogene whose amplification drives proliferation and transformation, motivating mechanistic dissection of its growth-promoting activity.","evidence":"Overexpression/knockdown with colony formation and anchorage-independent growth assays","pmids":["16172393"],"confidence":"Medium","gaps":["Molecular mechanism of growth promotion not defined","Link to chromatin remodeling not established"]},{"year":2008,"claim":"Identified the core RSF complex by showing RSF1 binds SNF2H/SMARCA5, stabilizes it, and drives its nuclear localization, defining RSF1 as the targeting subunit of an ISWI remodeler.","evidence":"Co-IP, in vitro competition assay with domain mapping, immunofluorescence colocalization","pmids":["18519663"],"confidence":"High","gaps":["Genomic targets of the complex not mapped","Remodeling biochemistry not reconstituted in this study"]},{"year":2009,"claim":"Linked RSF complex integrity to chemoresistance, showing the RSF1–SNF2H interaction is required for paclitaxel resistance and is therefore a functional, not incidental, partnership.","evidence":"siRNA, overexpression, complex disruption with drug resistance assays in ovarian cancer cells","pmids":["19190325"],"confidence":"Medium","gaps":["Downstream effectors of resistance not identified","Single cancer context"]},{"year":2010,"claim":"Connected RSF1 overexpression to genomic instability, showing that excess RSF complex activity induces strand breaks and activates the ATM-CHK2-p53 DDR, explaining its oncogenic instability phenotype.","evidence":"Ectopic expression, comet assay, γH2AX IF, pathway analysis with TP53 KO and ATM inhibition","pmids":["20923775"],"confidence":"High","gaps":["Direct mechanism producing breaks not defined","RSF1's role in normal (non-overexpressed) repair untested here"]},{"year":2013,"claim":"Defined RSF1 as a direct DSB repair factor: it accumulates at breaks via ATM, interacts with ATM, deposits CENP-S/CENP-X to promote NHEJ through XRCC4, and recruits RPA32/Rad51 for HR.","evidence":"Laser microirradiation, live-cell imaging, siRNA, ATM inhibition, recruitment and epistasis assays","pmids":["24351651","23974106"],"confidence":"High","gaps":["How RSF1 selects between NHEJ and HR not resolved","Chromatin remodeling step at breaks not directly visualized"]},{"year":2013,"claim":"Identified cyclin E1 as an RSF1 partner that, in TP53-mutant cells, activates CDK2 and drives tumorigenesis, providing a distinct oncogenic mechanism beyond chromatin remodeling.","evidence":"Co-IP/mass spectrometry, domain mapping, CDK2 kinase assay, xenograft","pmids":["23378270"],"confidence":"High","gaps":["Whether cyclin E1 binding depends on RSF complex unknown","Relationship to genomic instability phenotype not integrated"]},{"year":2013,"claim":"Showed RSF1 bridges the HBx viral protein to the mitotic checkpoint protein hBubR1 at kinetochores, linking RSF1 to chromosome segregation control.","evidence":"Co-IP, siRNA, deletion mutant analysis, kinetochore IF","pmids":["23536579"],"confidence":"Medium","gaps":["Endogenous (non-viral) function at the checkpoint not established here","Structural basis of bridging unknown"]},{"year":2014,"claim":"Refined the DSB model by establishing that RSF1–ATM interaction drives CENP-S/X loading that regulates FANCD2/FANCI monoubiquitination, with RSF1 needed for repair but not checkpoint signaling.","evidence":"Reciprocal Co-IP, siRNA, microirradiation recruitment assays, HR/NHEJ reporter epistasis","pmids":["24800743"],"confidence":"High","gaps":["How CENP-S/X feeds into the Fanconi pathway mechanistically unclear","Distinct repair vs. checkpoint separation of function not fully resolved"]},{"year":2015,"claim":"Established RSF1 as a kinetochore platform for PLK1, showing CDK1 phosphorylation at Ser1375 recruits PLK1 and a PLK1 feedback phosphorylation at Ser1359 stabilizes it, governing chromosome alignment.","evidence":"In vitro CDK1/PLK1 kinase assays, phosphomutant rescue, siRNA, live-cell imaging","pmids":["26259146"],"confidence":"High","gaps":["Connection to RSF complex remodeling at kinetochores not defined","Spatial regulation of the axis not yet established at this stage"]},{"year":2018,"claim":"Demonstrated RSF1 functions as a histone-modification regulator at centromeres by recruiting HDAC1 to deacetylate H2A-K118, enabling H2A-T120 phosphorylation and Sgo1 loading for accurate segregation.","evidence":"RSF1 knockout, Co-IP, ChIP, IF, HDAC1 centromeric tethering rescue","pmids":["30242288"],"confidence":"High","gaps":["How RSF1 spatially targets HDAC1 to centromeres unclear","Crosstalk with the PLK1/Aurora B axis not yet integrated"]},{"year":2018,"claim":"Extended RSF1's transcriptional role to p53 signaling, showing it is required for p53/p300 recruitment and H3 acetylation at p53 target promoters in vivo following DNA damage.","evidence":"Neural-specific Rsf1 knockout mouse, ChIP, transcriptome analysis","pmids":["30348983"],"confidence":"High","gaps":["Direct vs. indirect scaffolding of p53/p300 not dissected here","Specific target gene mechanisms not detailed"]},{"year":2018,"claim":"Revealed post-translational control of RSF1 abundance during damage: SNF2H stabilizes RSF1 while ATM phosphorylation at SQ sites destabilizes it, showing temporal level control is required for repair.","evidence":"Western blot under damage conditions, siRNA, phosphomutant overexpression, ATM manipulation, repair assay","pmids":["29385673"],"confidence":"Medium","gaps":["Degradation machinery acting on phospho-RSF1 not identified","Quantitative kinetics of level changes not defined"]},{"year":2021,"claim":"Unified the RSF1-HDAC1 histone crosstalk at DSBs, showing H2A(X)-K118 deacetylation is required for H2A-K119 ubiquitination, γH2AX spreading, MDC1 recruitment, and damage-site transcriptional repression.","evidence":"RSF1 depletion, phospho/acetyl histone mutants, ChIP, IF, γH2AX analysis","pmids":["34850117"],"confidence":"High","gaps":["Identity of the K119 ubiquitin ligase recruited downstream not defined here","Generality across chromatin contexts untested"]},{"year":2021,"claim":"Defined the spatial logic of the RSF1-PLK1 axis in mitosis, showing it activates Aurora B (Thr236) at centromeres for error correction and relocates to kinetochores upon attachment, controlled by H3-S28 phosphorylation.","evidence":"In vitro kinase assays, structural modeling, phosphomutants, IF, siRNA, live-cell imaging","pmids":["34635673"],"confidence":"High","gaps":["Trigger coupling attachment status to RSF1 movement not fully mechanistic","How remodeling activity contributes to relocation unknown"]},{"year":2021,"claim":"Linked RSF1 to a pro-angiogenic transcriptional program in cancer, showing it cotransactivates the IL1B promoter with SNF2H and CEBP/β to drive IL-1β-mediated angiogenesis.","evidence":"siRNA, RT-PCR, reporter assay, IL-1β ELISA, angiogenesis assay, xenograft","pmids":["33496909"],"confidence":"Medium","gaps":["Direct promoter occupancy mechanism not fully mapped","Single tumor type (myxofibrosarcoma)"]},{"year":2023,"claim":"Identified the molecular basis for RSF1 chromatin targeting, showing its UAB domain reads H2AK119ub and is required for recruitment to Polycomb-marked target genes in development.","evidence":"Xenopus morpholino knockdown, deletion-mutant rescue, ectopic H2AK119ub deposition, immunoprecipitation","pmids":["37529237"],"confidence":"Medium","gaps":["Structural details of UAB-ubiquitin recognition not resolved","Generality to human RSF1 targeting not directly tested"]},{"year":2024,"claim":"Detailed RSF1's coactivator scaffolding at CDKN1A, showing it promotes p300 enhancer binding and FACT (SSRP1/SPT16) promoter recruitment to support p53-dependent p21 transcription.","evidence":"Co-IP (RSF1-p300), ChIP in RSF1 KO cells, Western blot","pmids":["39579530"],"confidence":"Medium","gaps":["Order of p300 and FACT recruitment not resolved","Whether SNF2H remodeling is required not tested"]},{"year":2025,"claim":"Showed RSF1 itself is a regulated acetylation substrate, with KAT8 acetylating RSF1 at K1050 in a pathway linked to heterochromatin loss and skin aging, governed upstream by FTO/m6A control of KAT8.","evidence":"RNA-seq, MeRIP-seq, acetylation proteomics, siRNA/inhibitor, m6A assays, Western blot","pmids":["40636284"],"confidence":"Medium","gaps":["Functional consequence of K1050 acetylation on RSF activity not dissected","Direct causality between RSF1 acetylation and heterochromatin loss not established"]},{"year":2025,"claim":"Quantified the kinetics of RSF1/CENP-S/CENP-X at breaks, placing their simultaneous arrival (~100 s) downstream of ATM and RNF8-RNF168 across cell cycle phases, temporally anchoring RSF1 to early DSB nucleosome remodeling.","evidence":"Live-cell microirradiation, quantitative time-course imaging, cell cycle analysis","pmids":["40450933"],"confidence":"Medium","gaps":["Mechanism of co-recruitment as a unit not defined","Removal kinetics determinants unknown"]},{"year":null,"claim":"How RSF1 integrates its remodeling, histone-reading, and kinase-scaffolding functions into a single regulated platform—and how acetylation/phosphorylation of RSF1 itself toggles between these roles—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of full-length RSF1 with its modifications","Switch between repair, mitotic, and transcriptional roles uncoordinated in current data","Reconstitution of UAB-directed targeting with SNF2H remodeling missing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[16,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,20,18]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[19,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,12,20]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,9,16]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13,20]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[12,15,17]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,9,11,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,17,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,16,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,20,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,13]}],"complexes":["RSF complex (RSF1-SNF2H/SMARCA5)"],"partners":["SMARCA5","ATM","PLK1","HDAC1","EP300","CCNE1","CEBPB","BUB1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96T23","full_name":"Remodeling and spacing factor 1","aliases":["HBV 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25777942","citation_count":1,"is_preprint":false},{"pmid":"28146553","id":"PMC_28146553","title":"Correction: The RSF1 Histone-Remodelling Factor Facilitates DNA Double Strand Break Repair by Recruiting Centromeric and Fanconi Anaemia Proteins.","date":"2017","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/28146553","citation_count":1,"is_preprint":false},{"pmid":"41949721","id":"PMC_41949721","title":"RSF-1/hSNF2H Promotes the Proliferation and Migration of Adenoid Cystic Cancer Cells.","date":"2026","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41949721","citation_count":0,"is_preprint":false},{"pmid":"40979215","id":"PMC_40979215","title":"Correction to \"Depletion of Fat Mass and Obesity-Associated Protein (FTO) Drives Heterochromatin Loss via Lysine Acetyltransferase 8 (KAT8)-Mediated Remodeling and Spacing Factor 1 (RSF1) Acetylation in Skin Aging\".","date":"2025","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/40979215","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37162,"output_tokens":5929,"usd":0.10021,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14549,"output_tokens":6418,"usd":0.116598,"stage2_stop_reason":"end_turn"},"total_usd":0.216808,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"HBXAP (RSF1) physically interacts with hepatitis B virus X protein (pX) in vitro and in vivo via the HBXAP region containing the PHD finger domain. This interaction coactivates HBV transcription and NF-κB-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, transcription reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding with functional transcription assay, single lab\",\n      \"pmids\": [\"11788598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HBXAP (RSF1) possesses intrinsic transcriptional repression activity when recruited to DNA via GAL4; the PHD finger domain alone is sufficient for this repression activity.\",\n      \"method\": \"GAL4 fusion transcription reporter assay, deletion mutagenesis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reporter assay with domain mutagenesis, single lab\",\n      \"pmids\": [\"11944984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HBXAP (RSF1) represses NF-κB-mediated gene activation in a dose-dependent manner; HBXAP and NF-κB colocalize at the nuclear matrix with direct physical interaction. A nuclear matrix targeting sequence (aa 688–722, coiled-coil region) and the PHD finger domain are both required for this repression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, reporter gene assay, deletion mutagenesis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, colocalization, and functional reporter with domain mapping, single lab\",\n      \"pmids\": [\"15242768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RSF1 (HBXAP) overexpression stimulates cell proliferation and confers serum-independent and anchorage-independent growth in non-neoplastic cells; RSF1 knockdown inhibits growth in cells with RSF1 amplification.\",\n      \"method\": \"Overexpression/knockdown in cell lines, colony formation and growth assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"16172393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RSF1 interacts with hSNF2H (SMARCA5) to form a chromatin remodeling complex (RSF complex). Ectopic RSF1 expression upregulates hSNF2H protein levels and translocates hSNF2H to the nucleus where it colocalizes with RSF1. The hSNF2H binding site maps to the Rsf-D4 fragment of RSF1 by coimmunoprecipitation and in vitro competition assay.\",\n      \"method\": \"Co-immunoprecipitation, in vitro competition assay, immunofluorescence colocalization, deletion mutagenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro competition assay with domain mapping plus reciprocal Co-IP and colocalization, replicated across multiple studies\",\n      \"pmids\": [\"18519663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RSF1 promotes paclitaxel resistance in ovarian cancer cells; this resistance requires formation of the RSF1/hSNF2H complex, as disruption of hSNF2H or the RSF1-hSNF2H interaction restores paclitaxel sensitivity.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, drug resistance assays, disruption of complex\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with functional phenotype and complex disruption experiment, single lab\",\n      \"pmids\": [\"19190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RSF1 overexpression induces DNA strand breaks, nuclear γH2AX foci, and activates the ATM-CHK2-p53-p21 DNA damage response pathway. Formation of a functional RSF complex with SNF2H is required for RSF1 to trigger this DDR. Chronic RSF1 expression leads to chromosomal aberrations, c-myc amplification, and CDKN2A/B deletion.\",\n      \"method\": \"Ectopic expression, deletion mutagenesis, gene knockdown, comet assay, γH2AX immunofluorescence, chromosomal analysis, TP53 knockout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (comet assay, γH2AX, pathway analysis, genetic epistasis with TP53 KO and ATM inhibitor), single lab with rigorous controls\",\n      \"pmids\": [\"20923775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RSF1 interacts with cyclin E1 as identified by co-immunoprecipitation followed by nanoelectrospray mass spectrometry. Ectopic co-expression of RSF1 and cyclin E1 in TP53-mutant cells activates CDK2 and promotes cellular proliferation and tumor formation; the cyclin E1-binding site maps to the first 441 amino acids of RSF1.\",\n      \"method\": \"Co-immunoprecipitation, nanoelectrospray mass spectrometry, ectopic expression, domain mapping, CDK2 kinase assay, xenograft\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP/MS identification with domain mapping, functional validation by kinase assay and in vivo tumor formation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23378270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RSF1 accumulates at DNA double-strand break (DSB) sites in an ATM-dependent manner; putative ATM phosphorylation sites (pSQ motifs) on RSF1 are required for its DSB accumulation. RSF1 depletion attenuates DNA damage checkpoint signaling and reduces cell survival after damage. RSF1 promotes homologous recombination repair by recruiting resection factors RPA32 and Rad51.\",\n      \"method\": \"Laser microirradiation, live-cell imaging, immunofluorescence, siRNA depletion, ATM inhibition, RPA32/Rad51 recruitment assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell localization with functional consequence, domain mutagenesis, single lab\",\n      \"pmids\": [\"24351651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RSF1 deposits centromere proteins CENP-S and CENP-X at DNA DSB sites to promote NHEJ. CENP-S and CENP-X in turn facilitate assembly of NHEJ factor XRCC4 at damaged chromatin. RSF1 also promotes HR repair independently of CENP-S/CENP-X. SMARCA5 regulates RNF168-dependent ubiquitin response (BRCA1 recruitment) but RSF1 is dispensable for this.\",\n      \"method\": \"siRNA knockdown, laser microirradiation, immunofluorescence recruitment assay, IR survival assay, epistasis analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple knockdowns, live-cell recruitment assays, independently replicated in part by Pessina 2014 (PMID 24800743)\",\n      \"pmids\": [\"23974106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBxAPα/RSF1 mediates interaction between HBx viral protein and hBubR1 at the chromatin fraction during mitosis. RSF1 depletion abolishes the HBx-hBubR1 interaction and impairs HBx targeting to kinetochores. HBx binding to hBubR1 (stabilized by RSF1) reduces hBubR1-Cdc20 binding and increases mitotic aberrations.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, deletion mutant analysis, kinetochore immunofluorescence\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional epistasis, single lab\",\n      \"pmids\": [\"23536579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RSF1 physically interacts with ATM in a manner dependent on DSBs and ATM kinase activity. RSF1 is required for ATM-dependent recruitment of CENP-S/MHF1 and CENP-X/MHF2 to DSBs. These proteins in turn regulate mono-ubiquitination of Fanconi Anaemia proteins FANCD2 and FANCI. RSF1 is required for efficient DSB repair via both end-joining and homology-directed repair but is not required for checkpoint signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, laser microirradiation, immunofluorescence recruitment assay, epistasis with HR and NHEJ reporters\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for ATM interaction, multiple recruitment assays, epistasis analysis, independent replication of CENP-S/X loading consistent with PMID 23974106\",\n      \"pmids\": [\"24800743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RSF1 localizes at mitotic kinetochores and directly binds PLK1. CDK1 phosphorylates RSF1 at Ser1375, which is necessary for PLK1 recruitment to kinetochores. Subsequently PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition. RSF1 depletion causes chromosome misalignment phenotype mimicking PLK1 knockdown; rescued by RSF1 S1375D or S1359D but not S1375A phospho-mutants.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, phosphomutant rescue, in vitro kinase assay (CDK1 and PLK1), live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus genetic rescue experiments, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"26259146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RSF1 is required for p53-dependent gene transcription in response to DNA strand breaks. RSF1 deficiency reduces binding of the p53/p300 complex and subsequent H3 acetylation at p53 target gene promoters, causing reduced expression of p53 downstream genes.\",\n      \"method\": \"Neural-specific Rsf1 knockout mouse, chromatin immunoprecipitation, transcriptome analysis, Western blot, immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo knockout with chromatin immunoprecipitation and genome-wide transcriptome analysis, multiple orthogonal methods\",\n      \"pmids\": [\"30348983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RSF1 protein levels are transiently upregulated in response to DNA damage at the post-translational level (without changes in mRNA). SNF2H binding partner stabilizes RSF1 protein; ATM-mediated phosphorylation of RSF1 at three SQ sites (RSF1-3SA mutant) destabilizes the protein. Proper temporal regulation of RSF1 levels by SNF2H and ATM is essential for efficient DSB repair.\",\n      \"method\": \"Western blot under various DNA damage conditions, siRNA knockdown, phosphomutant overexpression, ATM kinase manipulation, DSB repair assay\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant analysis with functional repair assay, single lab, multiple conditions\",\n      \"pmids\": [\"29385673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RSF1 recruits HDAC1 to centromeres, where HDAC1 counteracts TIP60-mediated acetylation of histone H2A at K118. This deacetylation enables accumulation of H2A phosphorylation at T120 (by Bub1) and Sgo1 deposition at centromeres, which is required for faithful chromosome segregation. Centromeric HDAC1 tethering prevents premature chromatid separation in RSF1 knockout cells.\",\n      \"method\": \"Co-immunoprecipitation, RSF1 knockout, chromatin immunoprecipitation, immunofluorescence, rescue experiments with HDAC1 centromeric tethering\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic knockout with ChIP, functional rescue, histone modification crosstalk established by multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"30242288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under DNA damage, RSF1 recruits HDAC1 to DSB sites. The RSF1-HDAC1 complex deacetylates H2A(X) at K118, which is required for H2A ubiquitination at K119 (H2A-K119ub) and subsequent transcriptional repression at DNA lesions. Deacetylation of H2AX-K118 also enables γH2AX propagation and MDC1 recruitment, promoting DNA repair. H2A-K118Q acetylation mimetic suppresses H2A-K119ub and impairs repair.\",\n      \"method\": \"RSF1 depletion, phospho/acetyl mutant analysis, chromatin immunoprecipitation, immunofluorescence, γH2AX analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic dissection with multiple histone mutants, ChIP, and functional repair readouts in single rigorous study\",\n      \"pmids\": [\"34850117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RSF1 PLK1-axis at centromeres creates an activating phosphorylation on Aurora B at Thr236 (in the activation loop), which is indispensable for Aurora B activation and subsequent microtubule destabilization in error correction. Under full microtubule-kinetochore attachment, RSF1-PLK1 moves to kinetochores, halts Aurora B activation, and phosphorylates BubR1. Aurora B-mediated phosphorylation of centromeric histone H3 at Ser28 triggers the spatial RSF1-PLK1 movement from centromeres to kinetochores.\",\n      \"method\": \"In vitro kinase assay, structural modeling, phosphomutant analysis, immunofluorescence, siRNA depletion, live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with structural modeling and multiple phosphomutant validations, multiple orthogonal methods\",\n      \"pmids\": [\"34635673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RSF1 requires hSNF2H and CEBP/β to cotransactivate the IL1B promoter, increasing IL-1β mRNA, secretion, and downstream angiogenic capacity in myxofibrosarcoma cells. RSF1-driven angiogenesis is counteracted by IL1B knockdown and IL-1β-neutralizing antibodies.\",\n      \"method\": \"siRNA knockdown, RT-PCR profiling, chromatin reporter assay, IL-1β ELISA, angiogenesis assay, in vivo xenograft\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter activation with co-factor dependency established, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"33496909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RSF1 acts as a reader of histone H2A lysine 119 ubiquitination (H2AK119ub). The UAB domain of RSF1 is required to recognize H2AK119ub nucleosomes; deletion of the UAB domain abolishes the ability of RSF1 to rescue developmental defects in Xenopus rsf1 morphants. Ectopic deposition of H2AK119ub recruits RSF1 to the Smad2 target gene gsc.\",\n      \"method\": \"Xenopus laevis morpholino knockdown, rescue with deletion mutants, in vivo H2AK119ub deposition using ring1a-smad2 fusion, immunoprecipitation\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion rescue experiments in Xenopus with ectopic deposition validation, single lab\",\n      \"pmids\": [\"37529237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RSF1 promotes p53-dependent p21 (CDKN1A) gene transcription by facilitating accumulation of p300 acetyltransferase at the enhancer and FACT complex (SSRP1, SPT16) at the promoter of CDKN1A. RSF1 depletion reduces acetylated-K382 p53 levels and decreases p300 and TBP binding along with reduced H3K27ac and H3K4me1 at the CDKN1A locus.\",\n      \"method\": \"Co-immunoprecipitation (RSF1 with p300), chromatin immunoprecipitation, RSF1 knockout cells, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with KO cells, single lab, multiple chromatin marks analyzed\",\n      \"pmids\": [\"39579530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT8 acetyltransferase acetylates RSF1 at K1050, and this acetylation is associated with heterochromatin loss and cellular senescence during skin aging. FTO depletion reduces KAT8 mRNA stability via m6A-YTHDF2 pathway, leading to reduced KAT8 and downstream RSF1 K1050 acetylation.\",\n      \"method\": \"RNA-seq, MeRIP-seq, acetylation proteomics, siRNA/inhibitor knockdown, m6A modification assays, Western blot\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific acetylation identified by proteomics with functional pathway validation, single lab\",\n      \"pmids\": [\"40636284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RSF1 and CENP-S/CENPX are recruited to DSBs with a half-time of ~100 s and removed with a half-time of ~2000 s. Recruitment occurs in G1, S, and G2 phases, with stronger/delayed enrichment in G2. RSF1/CENP-S/CENPX arrive simultaneously after ATM activation and RNF8-RNF168 activity, temporally placing them at the time of nucleosome remodeling during early DSB response.\",\n      \"method\": \"Live-cell microirradiation, quantitative fluorescence time-course imaging, cell cycle phase analysis\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live-cell kinetics with cell cycle analysis, single lab\",\n      \"pmids\": [\"40450933\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RSF1 (HBXAP) is a subunit of the ISWI-family RSF chromatin remodeling complex, where it partners with the ATPase SNF2H/SMARCA5; it functions as a reader of H2AK119ub (via its UAB domain), recruits HDAC1 to centromeres and DSB sites to coordinate histone H2A deacetylation (K118) enabling H2A-K119 ubiquitination and γH2AX propagation, deposits centromere proteins CENP-S/X at DSBs to promote NHEJ via XRCC4, recruits PLK1 to kinetochores through CDK1-mediated Ser1375 phosphorylation to regulate Aurora B activity and faithful chromosome segregation, facilitates p53-dependent transcription by scaffolding p300 and FACT at target gene loci, and when overexpressed drives genomic instability via excessive RSF activity, paclitaxel/cisplatin resistance through NF-κB pathway activation, and IL-1β-mediated angiogenesis through co-activation of the IL1B promoter with CEBP/β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RSF1 (HBXAP) is the substrate-targeting subunit of the ISWI-family RSF chromatin remodeling complex, coupling nucleosome remodeling to DNA damage repair, mitotic chromosome segregation, and p53-dependent transcription [#4, #6, #15]. It binds the ATPase SNF2H/SMARCA5 through its Rsf-D4 region, an interaction that stabilizes RSF1 protein, redistributes SNF2H to the nucleus, and is obligatory for RSF complex remodeling activity [#4, #14]. At DNA double-strand breaks RSF1 accumulates in an ATM-dependent manner via phosphorylated SQ motifs, physically engages ATM, and deposits the centromere proteins CENP-S/CENP-X to drive both NHEJ (through XRCC4 assembly) and homology-directed repair, while also recruiting resection factors RPA32 and Rad51 [#8, #9, #11, #22]. RSF1 recruits HDAC1 to both centromeres and break sites, where deacetylation of histone H2A(X)-K118 licenses H2A-K119 ubiquitination, γH2AX propagation, and MDC1 recruitment, and at centromeres enables H2A-T120 phosphorylation and Sgo1 loading for accurate chromatid cohesion [#15, #16]. In mitosis, CDK1-mediated phosphorylation of RSF1 at Ser1375 recruits PLK1 to kinetochores, and the RSF1–PLK1 axis spatially regulates Aurora B activation (via Thr236) for error correction and faithful chromosome segregation [#12, #17]. RSF1 reads H2AK119ub through its UAB domain, linking it to Polycomb-marked chromatin [#19]. RSF1 also scaffolds p53/p300 and the FACT complex at target loci such as CDKN1A to support p53-dependent transcription following DNA damage [#13, #20]. When overexpressed, RSF1 drives genomic instability, anchorage-independent growth, and chemoresistance, and cooperates with cyclin E1 to activate CDK2 in TP53-mutant cells [#3, #5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established RSF1/HBXAP as a chromatin-associated transcriptional regulator able to coactivate viral and NF-κB transcription and to repress transcription via its PHD finger, framing it as a chromatin-acting protein before its remodeling role was known.\",\n      \"evidence\": \"Co-IP and in vitro binding with HBV pX plus GAL4 fusion reporter and deletion mutagenesis in cell lines\",\n      \"pmids\": [\"11788598\", \"11944984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the remodeling complex or ATPase partner\", \"Mechanism of transcriptional effect through chromatin not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized RSF1 to the nuclear matrix and mapped distinct domains (coiled-coil targeting sequence and PHD finger) required for NF-κB repression, refining its transcriptional regulatory architecture.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, reporter assays with deletion mutagenesis\",\n      \"pmids\": [\"15242768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect NF-κB regulation not resolved\", \"Relationship to remodeling activity unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that RSF1 functions as an oncogene whose amplification drives proliferation and transformation, motivating mechanistic dissection of its growth-promoting activity.\",\n      \"evidence\": \"Overexpression/knockdown with colony formation and anchorage-independent growth assays\",\n      \"pmids\": [\"16172393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of growth promotion not defined\", \"Link to chromatin remodeling not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the core RSF complex by showing RSF1 binds SNF2H/SMARCA5, stabilizes it, and drives its nuclear localization, defining RSF1 as the targeting subunit of an ISWI remodeler.\",\n      \"evidence\": \"Co-IP, in vitro competition assay with domain mapping, immunofluorescence colocalization\",\n      \"pmids\": [\"18519663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genomic targets of the complex not mapped\", \"Remodeling biochemistry not reconstituted in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked RSF complex integrity to chemoresistance, showing the RSF1–SNF2H interaction is required for paclitaxel resistance and is therefore a functional, not incidental, partnership.\",\n      \"evidence\": \"siRNA, overexpression, complex disruption with drug resistance assays in ovarian cancer cells\",\n      \"pmids\": [\"19190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of resistance not identified\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected RSF1 overexpression to genomic instability, showing that excess RSF complex activity induces strand breaks and activates the ATM-CHK2-p53 DDR, explaining its oncogenic instability phenotype.\",\n      \"evidence\": \"Ectopic expression, comet assay, γH2AX IF, pathway analysis with TP53 KO and ATM inhibition\",\n      \"pmids\": [\"20923775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism producing breaks not defined\", \"RSF1's role in normal (non-overexpressed) repair untested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined RSF1 as a direct DSB repair factor: it accumulates at breaks via ATM, interacts with ATM, deposits CENP-S/CENP-X to promote NHEJ through XRCC4, and recruits RPA32/Rad51 for HR.\",\n      \"evidence\": \"Laser microirradiation, live-cell imaging, siRNA, ATM inhibition, recruitment and epistasis assays\",\n      \"pmids\": [\"24351651\", \"23974106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RSF1 selects between NHEJ and HR not resolved\", \"Chromatin remodeling step at breaks not directly visualized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified cyclin E1 as an RSF1 partner that, in TP53-mutant cells, activates CDK2 and drives tumorigenesis, providing a distinct oncogenic mechanism beyond chromatin remodeling.\",\n      \"evidence\": \"Co-IP/mass spectrometry, domain mapping, CDK2 kinase assay, xenograft\",\n      \"pmids\": [\"23378270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cyclin E1 binding depends on RSF complex unknown\", \"Relationship to genomic instability phenotype not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed RSF1 bridges the HBx viral protein to the mitotic checkpoint protein hBubR1 at kinetochores, linking RSF1 to chromosome segregation control.\",\n      \"evidence\": \"Co-IP, siRNA, deletion mutant analysis, kinetochore IF\",\n      \"pmids\": [\"23536579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-viral) function at the checkpoint not established here\", \"Structural basis of bridging unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Refined the DSB model by establishing that RSF1–ATM interaction drives CENP-S/X loading that regulates FANCD2/FANCI monoubiquitination, with RSF1 needed for repair but not checkpoint signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, microirradiation recruitment assays, HR/NHEJ reporter epistasis\",\n      \"pmids\": [\"24800743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CENP-S/X feeds into the Fanconi pathway mechanistically unclear\", \"Distinct repair vs. checkpoint separation of function not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established RSF1 as a kinetochore platform for PLK1, showing CDK1 phosphorylation at Ser1375 recruits PLK1 and a PLK1 feedback phosphorylation at Ser1359 stabilizes it, governing chromosome alignment.\",\n      \"evidence\": \"In vitro CDK1/PLK1 kinase assays, phosphomutant rescue, siRNA, live-cell imaging\",\n      \"pmids\": [\"26259146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Connection to RSF complex remodeling at kinetochores not defined\", \"Spatial regulation of the axis not yet established at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated RSF1 functions as a histone-modification regulator at centromeres by recruiting HDAC1 to deacetylate H2A-K118, enabling H2A-T120 phosphorylation and Sgo1 loading for accurate segregation.\",\n      \"evidence\": \"RSF1 knockout, Co-IP, ChIP, IF, HDAC1 centromeric tethering rescue\",\n      \"pmids\": [\"30242288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RSF1 spatially targets HDAC1 to centromeres unclear\", \"Crosstalk with the PLK1/Aurora B axis not yet integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended RSF1's transcriptional role to p53 signaling, showing it is required for p53/p300 recruitment and H3 acetylation at p53 target promoters in vivo following DNA damage.\",\n      \"evidence\": \"Neural-specific Rsf1 knockout mouse, ChIP, transcriptome analysis\",\n      \"pmids\": [\"30348983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect scaffolding of p53/p300 not dissected here\", \"Specific target gene mechanisms not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed post-translational control of RSF1 abundance during damage: SNF2H stabilizes RSF1 while ATM phosphorylation at SQ sites destabilizes it, showing temporal level control is required for repair.\",\n      \"evidence\": \"Western blot under damage conditions, siRNA, phosphomutant overexpression, ATM manipulation, repair assay\",\n      \"pmids\": [\"29385673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation machinery acting on phospho-RSF1 not identified\", \"Quantitative kinetics of level changes not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Unified the RSF1-HDAC1 histone crosstalk at DSBs, showing H2A(X)-K118 deacetylation is required for H2A-K119 ubiquitination, γH2AX spreading, MDC1 recruitment, and damage-site transcriptional repression.\",\n      \"evidence\": \"RSF1 depletion, phospho/acetyl histone mutants, ChIP, IF, γH2AX analysis\",\n      \"pmids\": [\"34850117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the K119 ubiquitin ligase recruited downstream not defined here\", \"Generality across chromatin contexts untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the spatial logic of the RSF1-PLK1 axis in mitosis, showing it activates Aurora B (Thr236) at centromeres for error correction and relocates to kinetochores upon attachment, controlled by H3-S28 phosphorylation.\",\n      \"evidence\": \"In vitro kinase assays, structural modeling, phosphomutants, IF, siRNA, live-cell imaging\",\n      \"pmids\": [\"34635673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger coupling attachment status to RSF1 movement not fully mechanistic\", \"How remodeling activity contributes to relocation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RSF1 to a pro-angiogenic transcriptional program in cancer, showing it cotransactivates the IL1B promoter with SNF2H and CEBP/β to drive IL-1β-mediated angiogenesis.\",\n      \"evidence\": \"siRNA, RT-PCR, reporter assay, IL-1β ELISA, angiogenesis assay, xenograft\",\n      \"pmids\": [\"33496909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy mechanism not fully mapped\", \"Single tumor type (myxofibrosarcoma)\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the molecular basis for RSF1 chromatin targeting, showing its UAB domain reads H2AK119ub and is required for recruitment to Polycomb-marked target genes in development.\",\n      \"evidence\": \"Xenopus morpholino knockdown, deletion-mutant rescue, ectopic H2AK119ub deposition, immunoprecipitation\",\n      \"pmids\": [\"37529237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural details of UAB-ubiquitin recognition not resolved\", \"Generality to human RSF1 targeting not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Detailed RSF1's coactivator scaffolding at CDKN1A, showing it promotes p300 enhancer binding and FACT (SSRP1/SPT16) promoter recruitment to support p53-dependent p21 transcription.\",\n      \"evidence\": \"Co-IP (RSF1-p300), ChIP in RSF1 KO cells, Western blot\",\n      \"pmids\": [\"39579530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of p300 and FACT recruitment not resolved\", \"Whether SNF2H remodeling is required not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RSF1 itself is a regulated acetylation substrate, with KAT8 acetylating RSF1 at K1050 in a pathway linked to heterochromatin loss and skin aging, governed upstream by FTO/m6A control of KAT8.\",\n      \"evidence\": \"RNA-seq, MeRIP-seq, acetylation proteomics, siRNA/inhibitor, m6A assays, Western blot\",\n      \"pmids\": [\"40636284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of K1050 acetylation on RSF activity not dissected\", \"Direct causality between RSF1 acetylation and heterochromatin loss not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Quantified the kinetics of RSF1/CENP-S/CENP-X at breaks, placing their simultaneous arrival (~100 s) downstream of ATM and RNF8-RNF168 across cell cycle phases, temporally anchoring RSF1 to early DSB nucleosome remodeling.\",\n      \"evidence\": \"Live-cell microirradiation, quantitative time-course imaging, cell cycle analysis\",\n      \"pmids\": [\"40450933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of co-recruitment as a unit not defined\", \"Removal kinetics determinants unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RSF1 integrates its remodeling, histone-reading, and kinase-scaffolding functions into a single regulated platform—and how acetylation/phosphorylation of RSF1 itself toggles between these roles—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of full-length RSF1 with its modifications\", \"Switch between repair, mitotic, and transcriptional roles uncoordinated in current data\", \"Reconstitution of UAB-directed targeting with SNF2H remodeling missing\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [16, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 20, 18]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [19, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 12, 20]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 9, 16]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13, 20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [12, 15, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 9, 11, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 17, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 16, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 20, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"complexes\": [\"RSF complex (RSF1-SNF2H/SMARCA5)\"],\n    \"partners\": [\"SMARCA5\", \"ATM\", \"PLK1\", \"HDAC1\", \"EP300\", \"CCNE1\", \"CEBPB\", \"BUB1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}