{"gene":"SMARCC2","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2005,"finding":"BAF155 (SMARCC1) and BAF170 (SMARCC2) protein levels dictate the maximum cellular amount of BAF57; exogenous BAF57 triggers proteasome-dependent degradation of endogenous BAF57, and mapped protein-protein interaction domains between BAF57 and BAF155/BAF170 are required for this regulatory process.","method":"Exogenous expression of wild-type and deletion mutants, proteasome inhibitor assays, domain-mapping co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal domain-mapping pulldowns and proteasome inhibitor assays in single lab with multiple orthogonal methods","pmids":["16199878"],"is_preprint":false},{"year":2019,"finding":"SIRT6 mono-ADP-ribosylates BAF170 (SMARCC2), and this modification is required for SIRT6-mediated transcriptional activation of a subset of NRF2-responsive genes (e.g., HO-1) during oxidative stress; SIRT6 recruits BAF170 to the HO-1 enhancer, promotes RNA Pol II recruitment, and mediates formation of an active 10-kb chromatin loop at the HO-1 locus.","method":"SIRT6 separation-of-function mutants, in vitro mono-ADP-ribosylation assay, ChIP, chromatin conformation capture (3C/loop analysis), siRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic activity demonstrated with separation-of-function mutants, multiple orthogonal methods (in vitro ribosylation, ChIP, chromatin looping), single lab","pmids":["31216030"],"is_preprint":false},{"year":2016,"finding":"Conditional deletion of BAF170 (SMARCC2) in postnatal dentate gyrus depletes the pool of radial glial-like progenitor cells and promotes terminal astrocyte differentiation, resulting in spatial learning and memory deficits in mice.","method":"Conditional knockout mouse model, Morris water maze behavioral testing, histological analysis of neural progenitor cell populations","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype (progenitor depletion, astrocyte differentiation) and behavioral readout, single lab","pmids":["27392482"],"is_preprint":false},{"year":2015,"finding":"Knockdown of Baf170 (Smarcc2) during late-stage reprogramming improves iPSC colony formation efficiency and promotes complete reprogramming of partially reprogrammed cells (pre-iPSCs); Baf170 expression during reprogramming is regulated by Jak/Stat3 activity.","method":"shRNA-mediated knockdown in mouse reprogramming assay, iPSC colony counting, pre-iPSC reprogramming assay, Jak/Stat3 inhibitor treatment","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (iPSC reprogramming efficiency) plus pathway placement via Jak/Stat3 inhibition, single lab","pmids":["26121422"],"is_preprint":false},{"year":2021,"finding":"SMARCC2 physically binds c-Myc (co-immunoprecipitation) and its overexpression downregulates c-Myc expression, leading to reduced N-cadherin, vimentin, Snail, and β-catenin levels and elevated T-cadherin, thereby inhibiting EMT, cell migration, and invasion in glioma cells.","method":"Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression, wound-healing assay, Transwell invasion assay, Western blotting","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for binding plus OE/KD phenotypic assays, single lab, no mechanistic dissection of how SMARCC2 suppresses c-Myc","pmids":["34080022"],"is_preprint":false},{"year":2022,"finding":"SMARCC2 negatively regulates DKK1 transcription by closing DKK1 promoter chromatin accessibility, thereby preventing binding of the transcription factor EGR1 and inhibiting PI3K-AKT signaling to suppress glioblastoma proliferation; the SWIRM domain of SMARCC2 plays a more important role than the SANT domain in this chromatin remodeling function.","method":"SMARCC2 knockout and overexpression, ATAC-seq/chromatin accessibility assays, ChIP for EGR1 binding, siRNA knockdown of DKK1, Western blotting for PI3K-AKT pathway, domain deletion analysis, in vivo intracranial xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (chromatin accessibility, ChIP, domain mutants, in vivo), single lab","pmids":["36418306"],"is_preprint":false},{"year":2023,"finding":"FBXO28 (an E3 ubiquitin ligase) targets SMARCC2 for ubiquitination and proteasomal degradation; FBXO28-mediated degradation of SMARCC2 promotes pancreatic cancer cell proliferation, invasion, and metastasis, and overexpression of SMARCC2 reverses the pro-tumorigenic effects of FBXO28.","method":"Immunoprecipitation-mass spectrometry to identify SMARCC2 as FBXO28 substrate, co-immunoprecipitation, ubiquitination assays, rescue experiments with SMARCC2 overexpression, in vitro and in vivo functional assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by IP-MS, ubiquitination confirmed by Co-IP, phenotypic rescue validates functional relationship, single lab","pmids":["37348029"],"is_preprint":false},{"year":2024,"finding":"TRIM37 E3 ubiquitin ligase mediates ubiquitin-proteasome-dependent degradation of SMARCC2, and this degradation activates Wnt signaling, promoting sunitinib resistance in renal cell carcinoma cells.","method":"Co-immunoprecipitation to identify TRIM37-SMARCC2 interaction, western blot for SMARCC2 protein levels upon TRIM37 manipulation, functional assays (colony formation, sphere formation, drug sensitivity)","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, functional phenotype established but ubiquitination mechanism not directly demonstrated in abstract, single lab","pmids":["39349442"],"is_preprint":false},{"year":2024,"finding":"SMARCC2 silencing in breast cancer suppresses tumorigenesis and cancer stem cell features by reducing chromatin accessibility at enhancers of key oncogenic genes including PIK3CB, thereby downregulating the Ras-PI3K signaling pathway.","method":"SMARCC2 siRNA/shRNA knockdown, RNA-seq, ATAC-seq for chromatin accessibility, ChIP analysis, cell proliferation and mammosphere assays, xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ATAC-seq, ChIP, RNA-seq, in vivo xenograft) linking SMARCC2 to specific chromatin accessibility changes, single lab","pmids":["38852505"],"is_preprint":false},{"year":2025,"finding":"SMARCC2 (BAF170) physically binds HDAC2; Smarcc2 deficiency leads to reduced global histone acetylation and decreased H3K9ac at promoters of synaptic genes (Slc1a3/EAAT1, Slc6a1/GAT1, Slc32a1/VGAT), impairs GABAergic and glutamatergic synaptic currents in PFC pyramidal neurons, and causes working memory deficits; HDAC inhibition with romidepsin restores histone acetylation and working memory.","method":"Co-immunoprecipitation (SMARCC2-HDAC2 binding), ChIP-seq for SMARCC2 genome-wide binding, RNA-seq, ChIP for H3K9ac at synaptic gene promoters, electrophysiological recordings (GABAergic/glutamatergic currents), behavioral tests, romidepsin pharmacological rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP-seq, electrophysiology, behavioral rescue), preprint not yet peer-reviewed","pmids":["40492195"],"is_preprint":true},{"year":2018,"finding":"Pathogenic variants in SMARCC2 SANT and SWIRM domains (DNA-interacting domains) are associated with more severe neurodevelopmental phenotypes, indicating these domains are functionally critical for SMARCC2's role in the BAF complex during corticogenesis.","method":"Whole-exome sequencing of 15 affected individuals, genotype-phenotype correlation, domain mapping","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genotype-phenotype correlation provides indirect domain functional inference without direct in vitro domain assays in this paper","pmids":["30580808"],"is_preprint":false},{"year":2023,"finding":"N-terminal missense variants in SMARCC2 decrease protein expression to levels similar to likely gene-disrupting variants, as demonstrated by in vitro testing; non-truncating variants cluster in functional domains and disrupt BAF subunit interactions as assessed by co-immunoprecipitation and proximity-ligation assays.","method":"In vitro protein expression assays, 3D protein modeling, co-immunoprecipitation, proximity-ligation assays","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, proximity-ligation, protein expression assays) for variant functional testing, single lab","pmids":["37551667"],"is_preprint":false}],"current_model":"SMARCC2 (BAF170) is a core, invariant subunit of the mammalian BAF SWI/SNF chromatin remodeling complex whose levels are regulated by protein-protein interactions and ubiquitin-proteasome degradation (via FBXO28 and TRIM37); it is mono-ADP-ribosylated by SIRT6 to enable recruitment to gene enhancers and active chromatin loop formation for NRF2 target gene activation; it binds HDAC2 and regulates histone acetylation at synaptic gene promoters to support GABAergic and glutamatergic transmission and cognitive function; and through its SWIRM and SANT domains it remodels chromatin at target gene promoters (e.g., DKK1, PIK3CB) to regulate PI3K-AKT and Wnt/β-catenin signaling, with loss-of-function causing neural progenitor depletion, impaired reprogramming, and neurodevelopmental disorders."},"narrative":{"mechanistic_narrative":"SMARCC2 (BAF170) is a core subunit of the mammalian BAF (SWI/SNF) chromatin remodeling complex that controls chromatin accessibility at target promoters and enhancers to govern lineage-specific transcriptional programs [PMID:36418306, PMID:38852505]. Within the complex, SMARCC2 and its paralog BAF155 set the maximal cellular level of BAF57, an effect dependent on mapped protein-protein interaction domains and the proteasome, establishing SMARCC2 as a stoichiometry-determining scaffold [PMID:16199878]. SMARCC2 acts directly on chromatin through its SWIRM and SANT domains: it closes accessibility at the DKK1 promoter to block EGR1 binding and dampen PI3K-AKT signaling, with the SWIRM domain being especially important [PMID:36418306], and reduces enhancer accessibility at oncogenic loci such as PIK3CB to attenuate Ras-PI3K signaling [PMID:38852505]. Its activity is tuned by post-translational modification and turnover — SIRT6 mono-ADP-ribosylates SMARCC2 to recruit it to the HO-1 enhancer and form an active chromatin loop driving NRF2-responsive gene activation [PMID:31216030], while the E3 ligases FBXO28 and TRIM37 target SMARCC2 for ubiquitin-proteasome degradation, with loss of SMARCC2 promoting tumor progression and Wnt-driven drug resistance [PMID:37348029, PMID:39349442]. In the nervous system, SMARCC2 maintains neural progenitor pools [PMID:27392482] and binds HDAC2 to set histone acetylation at synaptic gene promoters, supporting GABAergic and glutamatergic transmission and memory [PMID:40492195]. Pathogenic SMARCC2 variants concentrated in the SANT and SWIRM domains cause neurodevelopmental disorders, acting through reduced protein expression and disrupted BAF subunit interactions [PMID:30580808, PMID:37551667].","teleology":[{"year":2005,"claim":"Established SMARCC2 as a stoichiometry-setting scaffold within BAF: its levels, together with BAF155, dictate how much BAF57 the cell can retain.","evidence":"Exogenous expression with deletion mutants, proteasome inhibitor assays, and domain-mapping co-IP","pmids":["16199878"],"confidence":"Medium","gaps":["Does not define the assembled BAF architecture in vivo","Mechanism by which excess BAF57 is selected for degradation not resolved"]},{"year":2015,"claim":"Showed SMARCC2 acts as a barrier to full reprogramming, placing its expression downstream of Jak/Stat3 during cell fate transitions.","evidence":"shRNA knockdown in mouse iPSC reprogramming assays with Jak/Stat3 inhibitor treatment","pmids":["26121422"],"confidence":"Medium","gaps":["Direct chromatin targets mediating the reprogramming block not identified","Whether the effect requires BAF complex integrity untested"]},{"year":2016,"claim":"Demonstrated a cell-intrinsic developmental requirement for SMARCC2 in maintaining neural progenitor pools and preventing premature astrocyte differentiation.","evidence":"Conditional knockout in postnatal dentate gyrus with histology and Morris water maze","pmids":["27392482"],"confidence":"Medium","gaps":["Molecular targets driving progenitor maintenance not defined","Chromatin remodeling activity not directly linked to the phenotype"]},{"year":2018,"claim":"Linked SMARCC2 to a human neurodevelopmental disorder and inferred that DNA-interacting SANT/SWIRM domains are functionally critical.","evidence":"Whole-exome sequencing of 15 individuals with genotype-phenotype correlation","pmids":["30580808"],"confidence":"Low","gaps":["Indirect domain inference without direct in vitro domain assays","Variant effect on remodeling activity not measured"]},{"year":2019,"claim":"Identified SMARCC2 as a SIRT6 mono-ADP-ribosylation substrate, providing a PTM mechanism that recruits it to enhancers and enables active chromatin loop formation for NRF2 target activation.","evidence":"SIRT6 separation-of-function mutants, in vitro ribosylation, ChIP, and 3C looping with siRNA knockdown","pmids":["31216030"],"confidence":"High","gaps":["Modified residue(s) on SMARCC2 not mapped","Generality beyond HO-1/NRF2 loci unknown"]},{"year":2021,"claim":"Provided a physical SMARCC2–c-Myc link and a tumor-suppressive role in glioma EMT, though mechanism of c-Myc suppression remained undissected.","evidence":"Single Co-IP plus overexpression/knockdown with migration and invasion assays","pmids":["34080022"],"confidence":"Low","gaps":["No reciprocal validation of the interaction","How SMARCC2 represses c-Myc not mechanistically resolved"]},{"year":2022,"claim":"Defined a direct chromatin-remodeling mechanism: SMARCC2 closes DKK1 promoter accessibility to block EGR1 binding and suppress PI3K-AKT signaling, with the SWIRM domain dominant over SANT.","evidence":"Knockout/overexpression, ATAC-seq, ChIP for EGR1, domain deletions, and intracranial xenografts","pmids":["36418306"],"confidence":"Medium","gaps":["Whether DKK1 regulation requires intact BAF complex not shown","Direct biochemical SWIRM activity not reconstituted"]},{"year":2023,"claim":"Established FBXO28 as an E3 ligase targeting SMARCC2 for proteasomal degradation, with restored SMARCC2 reversing pro-tumorigenic effects in pancreatic cancer.","evidence":"IP-MS substrate identification, co-IP, ubiquitination assays, and rescue with in vitro/in vivo assays","pmids":["37348029"],"confidence":"Medium","gaps":["Degron/recognition motif on SMARCC2 not mapped","Signals controlling FBXO28 activity unknown"]},{"year":2023,"claim":"Showed disease-associated N-terminal missense variants reduce SMARCC2 expression and disrupt BAF subunit interactions, clarifying a loss-of-function disease mechanism.","evidence":"In vitro expression assays, 3D modeling, co-IP, and proximity-ligation assays","pmids":["37551667"],"confidence":"Medium","gaps":["Functional remodeling consequences in neurons not assayed","Which specific subunit contacts are lost not fully enumerated"]},{"year":2024,"claim":"Extended the degradation paradigm: TRIM37-mediated SMARCC2 turnover activates Wnt signaling and drives sunitinib resistance in renal cell carcinoma.","evidence":"Co-IP, western blot of SMARCC2 upon TRIM37 manipulation, and drug-sensitivity/colony/sphere assays","pmids":["39349442"],"confidence":"Low","gaps":["Direct ubiquitination of SMARCC2 by TRIM37 not demonstrated","Single Co-IP without reciprocal validation"]},{"year":2024,"claim":"Generalized SMARCC2's enhancer-accessibility role to oncogenic loci, linking it to PIK3CB enhancer activity and Ras-PI3K signaling in breast cancer stemness.","evidence":"siRNA/shRNA knockdown, RNA-seq, ATAC-seq, ChIP, mammosphere assays, and xenografts","pmids":["38852505"],"confidence":"Medium","gaps":["Direct binding of SMARCC2 at the PIK3CB enhancer versus complex-mediated effect not separated","Context-dependence across tumor types unclear"]},{"year":2025,"claim":"Connected SMARCC2 to histone acetylation control at synaptic genes via HDAC2 binding, mechanistically linking its loss to synaptic and memory deficits reversible by HDAC inhibition.","evidence":"Co-IP, ChIP-seq, RNA-seq, H3K9ac ChIP, electrophysiology, behavior, and romidepsin rescue (preprint)","pmids":["40492195"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether SMARCC2 directly recruits HDAC2 to synaptic promoters versus indirect effect unresolved"]},{"year":null,"claim":"How SMARCC2's biochemical remodeling activity, PTM regulation, and degradation are integrated to select specific enhancers/promoters across distinct tissues remains unresolved.","evidence":"No single study reconstitutes SMARCC2-directed remodeling with defined targets across contexts","pmids":[],"confidence":"Low","gaps":["No structural model of SMARCC2 within an assembled BAF complex on chromatin","Modified residues and degrons not mapped","Rules governing tissue-specific target selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,9]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5,8,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,8]}],"complexes":["BAF (SWI/SNF) complex"],"partners":["SMARCC1","SMARCE1","SIRT6","FBXO28","TRIM37","HDAC2","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAQ2","full_name":"SWI/SNF complex subunit SMARCC2","aliases":["BRG1-associated factor 170","BAF170","SWI/SNF complex 170 kDa subunit","SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 2"],"length_aa":1214,"mass_kda":132.9,"function":"Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:11018012). Can stimulate the ATPase activity of the catalytic subunit of these complexes (PubMed:10078207). May be required for CoREST dependent repression of neuronal specific gene promoters in non-neuronal cells (PubMed:12192000). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8TAQ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMARCC2","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000139613","cell_line_id":"CID001678","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"ARID1A","stoichiometry":10.0},{"gene":"SMARCA4","stoichiometry":10.0},{"gene":"SMARCB1","stoichiometry":10.0},{"gene":"ACTL6A","stoichiometry":10.0},{"gene":"SMARCD2","stoichiometry":10.0},{"gene":"DPF2","stoichiometry":10.0},{"gene":"SMARCD1","stoichiometry":10.0},{"gene":"SMARCE1","stoichiometry":10.0},{"gene":"PHF10","stoichiometry":4.0},{"gene":"ARID1B","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001678","total_profiled":1310},"omim":[{"mim_id":"618362","title":"COFFIN-SIRIS SYNDROME 8; CSS8","url":"https://www.omim.org/entry/618362"},{"mim_id":"616333","title":"WNT SIGNALING PATHWAY ACTIVATING NONCODING RNA; WSPAR","url":"https://www.omim.org/entry/616333"},{"mim_id":"615514","title":"CYCLIN-DEPENDENT KINASE 12; CDK12","url":"https://www.omim.org/entry/615514"},{"mim_id":"611386","title":"ACTIVITY-DEPENDENT NEUROPROTECTOR HOMEOBOX; ADNP","url":"https://www.omim.org/entry/611386"},{"mim_id":"603544","title":"CYCLIN K; CCNK","url":"https://www.omim.org/entry/603544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMARCC2"},"hgnc":{"alias_symbol":["BAF170","Rsc8","CRACC2"],"prev_symbol":[]},"alphafold":{"accession":"Q8TAQ2","domains":[{"cath_id":"-","chopping":"1-137","consensus_level":"medium","plddt":92.2074,"start":1,"end":137},{"cath_id":"3.40.50.10190","chopping":"139-280","consensus_level":"medium","plddt":84.9535,"start":139,"end":280},{"cath_id":"1.10.10.10","chopping":"427-517","consensus_level":"high","plddt":94.279,"start":427,"end":517},{"cath_id":"1.10.10.60","chopping":"602-660","consensus_level":"high","plddt":80.2742,"start":602,"end":660},{"cath_id":"1.20.5","chopping":"683-732","consensus_level":"high","plddt":72.3362,"start":683,"end":732},{"cath_id":"1.20.5","chopping":"877-925","consensus_level":"medium","plddt":93.2943,"start":877,"end":925}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAQ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAQ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAQ2-F1-predicted_aligned_error_v6.png","plddt_mean":63.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMARCC2","jax_strain_url":"https://www.jax.org/strain/search?query=SMARCC2"},"sequence":{"accession":"Q8TAQ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAQ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAQ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAQ2"}},"corpus_meta":[{"pmid":"16199878","id":"PMC_16199878","title":"Regulating SWI/SNF subunit levels via protein-protein interactions and proteasomal degradation: BAF155 and BAF170 limit expression of BAF57.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16199878","citation_count":106,"is_preprint":false},{"pmid":"30580808","id":"PMC_30580808","title":"Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30580808","citation_count":76,"is_preprint":false},{"pmid":"31216030","id":"PMC_31216030","title":"SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31216030","citation_count":68,"is_preprint":false},{"pmid":"27392482","id":"PMC_27392482","title":"Ablation of BAF170 in Developing and Postnatal Dentate Gyrus Affects Neural Stem Cell Proliferation, Differentiation, and Learning.","date":"2016","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27392482","citation_count":40,"is_preprint":false},{"pmid":"29337109","id":"PMC_29337109","title":"Molecular mechanisms of lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis in gastric cancer.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29337109","citation_count":27,"is_preprint":false},{"pmid":"31308753","id":"PMC_31308753","title":"Plasma long noncoding RNAs PANDAR, FOXD2-AS1, and SMARCC2 as potential novel diagnostic biomarkers for gastric cancer.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31308753","citation_count":26,"is_preprint":false},{"pmid":"26121422","id":"PMC_26121422","title":"Knockdown of Brm and Baf170, Components of Chromatin Remodeling Complex, Facilitates Reprogramming of Somatic Cells.","date":"2015","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/26121422","citation_count":14,"is_preprint":false},{"pmid":"37551667","id":"PMC_37551667","title":"Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37551667","citation_count":12,"is_preprint":false},{"pmid":"34080022","id":"PMC_34080022","title":"SMARCC2 combined with c‑Myc inhibits the migration and invasion of glioma cells via modulation of the Wnt/β‑catenin signaling pathway.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34080022","citation_count":9,"is_preprint":false},{"pmid":"36418306","id":"PMC_36418306","title":"SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of 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: MN","url":"https://pubmed.ncbi.nlm.nih.gov/35536477","citation_count":3,"is_preprint":false},{"pmid":"38852505","id":"PMC_38852505","title":"SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38852505","citation_count":2,"is_preprint":false},{"pmid":"39349442","id":"PMC_39349442","title":"N6-methyladenosine-modified TRIM37 augments sunitinib resistance by promoting the ubiquitin-degradation of SmARCC2 and activating the Wnt signaling pathway in renal cell carcinoma.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39349442","citation_count":2,"is_preprint":false},{"pmid":"39901255","id":"PMC_39901255","title":"Identification and functional analysis of a novel SMARCC2 splicing variant in a family with syndromic neurodevelopmental disorder.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39901255","citation_count":2,"is_preprint":false},{"pmid":"41532374","id":"PMC_41532374","title":"Clinical and Genetic Analysis of SMARCC2-Related Diseases in Three Chinese Patients.","date":"2026","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41532374","citation_count":1,"is_preprint":false},{"pmid":"40492195","id":"PMC_40492195","title":"Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene Smarcc2 and its Rescue by Histone Deacetylase Inhibition.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40492195","citation_count":0,"is_preprint":false},{"pmid":"42091196","id":"PMC_42091196","title":"[Clinical characteristics and genetic analysis of a child with Coffin-Siris syndrome type 8 due to an intronic variant of SMARCC2 gene].","date":"2026","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/42091196","citation_count":0,"is_preprint":false},{"pmid":"41291750","id":"PMC_41291750","title":"Long-read sequencing identifies a novel de novo inversion in SMARCC2 in a pediatric patient with Coffin-siris syndrome 8: a case report.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41291750","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.29.656867","title":"Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene  <i>Smarcc2</i>  and its Rescue by Histone Deacetylase Inhibition","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.29.656867","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13237,"output_tokens":3238,"usd":0.04414,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10774,"output_tokens":3915,"usd":0.075872,"stage2_stop_reason":"end_turn"},"total_usd":0.120012,"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\": 2005,\n      \"finding\": \"BAF155 (SMARCC1) and BAF170 (SMARCC2) protein levels dictate the maximum cellular amount of BAF57; exogenous BAF57 triggers proteasome-dependent degradation of endogenous BAF57, and mapped protein-protein interaction domains between BAF57 and BAF155/BAF170 are required for this regulatory process.\",\n      \"method\": \"Exogenous expression of wild-type and deletion mutants, proteasome inhibitor assays, domain-mapping co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal domain-mapping pulldowns and proteasome inhibitor assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16199878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT6 mono-ADP-ribosylates BAF170 (SMARCC2), and this modification is required for SIRT6-mediated transcriptional activation of a subset of NRF2-responsive genes (e.g., HO-1) during oxidative stress; SIRT6 recruits BAF170 to the HO-1 enhancer, promotes RNA Pol II recruitment, and mediates formation of an active 10-kb chromatin loop at the HO-1 locus.\",\n      \"method\": \"SIRT6 separation-of-function mutants, in vitro mono-ADP-ribosylation assay, ChIP, chromatin conformation capture (3C/loop analysis), siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic activity demonstrated with separation-of-function mutants, multiple orthogonal methods (in vitro ribosylation, ChIP, chromatin looping), single lab\",\n      \"pmids\": [\"31216030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional deletion of BAF170 (SMARCC2) in postnatal dentate gyrus depletes the pool of radial glial-like progenitor cells and promotes terminal astrocyte differentiation, resulting in spatial learning and memory deficits in mice.\",\n      \"method\": \"Conditional knockout mouse model, Morris water maze behavioral testing, histological analysis of neural progenitor cell populations\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype (progenitor depletion, astrocyte differentiation) and behavioral readout, single lab\",\n      \"pmids\": [\"27392482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of Baf170 (Smarcc2) during late-stage reprogramming improves iPSC colony formation efficiency and promotes complete reprogramming of partially reprogrammed cells (pre-iPSCs); Baf170 expression during reprogramming is regulated by Jak/Stat3 activity.\",\n      \"method\": \"shRNA-mediated knockdown in mouse reprogramming assay, iPSC colony counting, pre-iPSC reprogramming assay, Jak/Stat3 inhibitor treatment\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (iPSC reprogramming efficiency) plus pathway placement via Jak/Stat3 inhibition, single lab\",\n      \"pmids\": [\"26121422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMARCC2 physically binds c-Myc (co-immunoprecipitation) and its overexpression downregulates c-Myc expression, leading to reduced N-cadherin, vimentin, Snail, and β-catenin levels and elevated T-cadherin, thereby inhibiting EMT, cell migration, and invasion in glioma cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression, wound-healing assay, Transwell invasion assay, Western blotting\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for binding plus OE/KD phenotypic assays, single lab, no mechanistic dissection of how SMARCC2 suppresses c-Myc\",\n      \"pmids\": [\"34080022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMARCC2 negatively regulates DKK1 transcription by closing DKK1 promoter chromatin accessibility, thereby preventing binding of the transcription factor EGR1 and inhibiting PI3K-AKT signaling to suppress glioblastoma proliferation; the SWIRM domain of SMARCC2 plays a more important role than the SANT domain in this chromatin remodeling function.\",\n      \"method\": \"SMARCC2 knockout and overexpression, ATAC-seq/chromatin accessibility assays, ChIP for EGR1 binding, siRNA knockdown of DKK1, Western blotting for PI3K-AKT pathway, domain deletion analysis, in vivo intracranial xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (chromatin accessibility, ChIP, domain mutants, in vivo), single lab\",\n      \"pmids\": [\"36418306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO28 (an E3 ubiquitin ligase) targets SMARCC2 for ubiquitination and proteasomal degradation; FBXO28-mediated degradation of SMARCC2 promotes pancreatic cancer cell proliferation, invasion, and metastasis, and overexpression of SMARCC2 reverses the pro-tumorigenic effects of FBXO28.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry to identify SMARCC2 as FBXO28 substrate, co-immunoprecipitation, ubiquitination assays, rescue experiments with SMARCC2 overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by IP-MS, ubiquitination confirmed by Co-IP, phenotypic rescue validates functional relationship, single lab\",\n      \"pmids\": [\"37348029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM37 E3 ubiquitin ligase mediates ubiquitin-proteasome-dependent degradation of SMARCC2, and this degradation activates Wnt signaling, promoting sunitinib resistance in renal cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation to identify TRIM37-SMARCC2 interaction, western blot for SMARCC2 protein levels upon TRIM37 manipulation, functional assays (colony formation, sphere formation, drug sensitivity)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, functional phenotype established but ubiquitination mechanism not directly demonstrated in abstract, single lab\",\n      \"pmids\": [\"39349442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMARCC2 silencing in breast cancer suppresses tumorigenesis and cancer stem cell features by reducing chromatin accessibility at enhancers of key oncogenic genes including PIK3CB, thereby downregulating the Ras-PI3K signaling pathway.\",\n      \"method\": \"SMARCC2 siRNA/shRNA knockdown, RNA-seq, ATAC-seq for chromatin accessibility, ChIP analysis, cell proliferation and mammosphere assays, xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ATAC-seq, ChIP, RNA-seq, in vivo xenograft) linking SMARCC2 to specific chromatin accessibility changes, single lab\",\n      \"pmids\": [\"38852505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMARCC2 (BAF170) physically binds HDAC2; Smarcc2 deficiency leads to reduced global histone acetylation and decreased H3K9ac at promoters of synaptic genes (Slc1a3/EAAT1, Slc6a1/GAT1, Slc32a1/VGAT), impairs GABAergic and glutamatergic synaptic currents in PFC pyramidal neurons, and causes working memory deficits; HDAC inhibition with romidepsin restores histone acetylation and working memory.\",\n      \"method\": \"Co-immunoprecipitation (SMARCC2-HDAC2 binding), ChIP-seq for SMARCC2 genome-wide binding, RNA-seq, ChIP for H3K9ac at synaptic gene promoters, electrophysiological recordings (GABAergic/glutamatergic currents), behavioral tests, romidepsin pharmacological rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP-seq, electrophysiology, behavioral rescue), preprint not yet peer-reviewed\",\n      \"pmids\": [\"40492195\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pathogenic variants in SMARCC2 SANT and SWIRM domains (DNA-interacting domains) are associated with more severe neurodevelopmental phenotypes, indicating these domains are functionally critical for SMARCC2's role in the BAF complex during corticogenesis.\",\n      \"method\": \"Whole-exome sequencing of 15 affected individuals, genotype-phenotype correlation, domain mapping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genotype-phenotype correlation provides indirect domain functional inference without direct in vitro domain assays in this paper\",\n      \"pmids\": [\"30580808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"N-terminal missense variants in SMARCC2 decrease protein expression to levels similar to likely gene-disrupting variants, as demonstrated by in vitro testing; non-truncating variants cluster in functional domains and disrupt BAF subunit interactions as assessed by co-immunoprecipitation and proximity-ligation assays.\",\n      \"method\": \"In vitro protein expression assays, 3D protein modeling, co-immunoprecipitation, proximity-ligation assays\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, proximity-ligation, protein expression assays) for variant functional testing, single lab\",\n      \"pmids\": [\"37551667\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMARCC2 (BAF170) is a core, invariant subunit of the mammalian BAF SWI/SNF chromatin remodeling complex whose levels are regulated by protein-protein interactions and ubiquitin-proteasome degradation (via FBXO28 and TRIM37); it is mono-ADP-ribosylated by SIRT6 to enable recruitment to gene enhancers and active chromatin loop formation for NRF2 target gene activation; it binds HDAC2 and regulates histone acetylation at synaptic gene promoters to support GABAergic and glutamatergic transmission and cognitive function; and through its SWIRM and SANT domains it remodels chromatin at target gene promoters (e.g., DKK1, PIK3CB) to regulate PI3K-AKT and Wnt/β-catenin signaling, with loss-of-function causing neural progenitor depletion, impaired reprogramming, and neurodevelopmental disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMARCC2 (BAF170) is a core subunit of the mammalian BAF (SWI/SNF) chromatin remodeling complex that controls chromatin accessibility at target promoters and enhancers to govern lineage-specific transcriptional programs [#5, #8]. Within the complex, SMARCC2 and its paralog BAF155 set the maximal cellular level of BAF57, an effect dependent on mapped protein-protein interaction domains and the proteasome, establishing SMARCC2 as a stoichiometry-determining scaffold [#0]. SMARCC2 acts directly on chromatin through its SWIRM and SANT domains: it closes accessibility at the DKK1 promoter to block EGR1 binding and dampen PI3K-AKT signaling, with the SWIRM domain being especially important [#5], and reduces enhancer accessibility at oncogenic loci such as PIK3CB to attenuate Ras-PI3K signaling [#8]. Its activity is tuned by post-translational modification and turnover — SIRT6 mono-ADP-ribosylates SMARCC2 to recruit it to the HO-1 enhancer and form an active chromatin loop driving NRF2-responsive gene activation [#1], while the E3 ligases FBXO28 and TRIM37 target SMARCC2 for ubiquitin-proteasome degradation, with loss of SMARCC2 promoting tumor progression and Wnt-driven drug resistance [#6, #7]. In the nervous system, SMARCC2 maintains neural progenitor pools [#2] and binds HDAC2 to set histone acetylation at synaptic gene promoters, supporting GABAergic and glutamatergic transmission and memory [#9]. Pathogenic SMARCC2 variants concentrated in the SANT and SWIRM domains cause neurodevelopmental disorders, acting through reduced protein expression and disrupted BAF subunit interactions [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established SMARCC2 as a stoichiometry-setting scaffold within BAF: its levels, together with BAF155, dictate how much BAF57 the cell can retain.\",\n      \"evidence\": \"Exogenous expression with deletion mutants, proteasome inhibitor assays, and domain-mapping co-IP\",\n      \"pmids\": [\"16199878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the assembled BAF architecture in vivo\", \"Mechanism by which excess BAF57 is selected for degradation not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SMARCC2 acts as a barrier to full reprogramming, placing its expression downstream of Jak/Stat3 during cell fate transitions.\",\n      \"evidence\": \"shRNA knockdown in mouse iPSC reprogramming assays with Jak/Stat3 inhibitor treatment\",\n      \"pmids\": [\"26121422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets mediating the reprogramming block not identified\", \"Whether the effect requires BAF complex integrity untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a cell-intrinsic developmental requirement for SMARCC2 in maintaining neural progenitor pools and preventing premature astrocyte differentiation.\",\n      \"evidence\": \"Conditional knockout in postnatal dentate gyrus with histology and Morris water maze\",\n      \"pmids\": [\"27392482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets driving progenitor maintenance not defined\", \"Chromatin remodeling activity not directly linked to the phenotype\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked SMARCC2 to a human neurodevelopmental disorder and inferred that DNA-interacting SANT/SWIRM domains are functionally critical.\",\n      \"evidence\": \"Whole-exome sequencing of 15 individuals with genotype-phenotype correlation\",\n      \"pmids\": [\"30580808\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect domain inference without direct in vitro domain assays\", \"Variant effect on remodeling activity not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SMARCC2 as a SIRT6 mono-ADP-ribosylation substrate, providing a PTM mechanism that recruits it to enhancers and enables active chromatin loop formation for NRF2 target activation.\",\n      \"evidence\": \"SIRT6 separation-of-function mutants, in vitro ribosylation, ChIP, and 3C looping with siRNA knockdown\",\n      \"pmids\": [\"31216030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modified residue(s) on SMARCC2 not mapped\", \"Generality beyond HO-1/NRF2 loci unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a physical SMARCC2–c-Myc link and a tumor-suppressive role in glioma EMT, though mechanism of c-Myc suppression remained undissected.\",\n      \"evidence\": \"Single Co-IP plus overexpression/knockdown with migration and invasion assays\",\n      \"pmids\": [\"34080022\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reciprocal validation of the interaction\", \"How SMARCC2 represses c-Myc not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a direct chromatin-remodeling mechanism: SMARCC2 closes DKK1 promoter accessibility to block EGR1 binding and suppress PI3K-AKT signaling, with the SWIRM domain dominant over SANT.\",\n      \"evidence\": \"Knockout/overexpression, ATAC-seq, ChIP for EGR1, domain deletions, and intracranial xenografts\",\n      \"pmids\": [\"36418306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DKK1 regulation requires intact BAF complex not shown\", \"Direct biochemical SWIRM activity not reconstituted\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established FBXO28 as an E3 ligase targeting SMARCC2 for proteasomal degradation, with restored SMARCC2 reversing pro-tumorigenic effects in pancreatic cancer.\",\n      \"evidence\": \"IP-MS substrate identification, co-IP, ubiquitination assays, and rescue with in vitro/in vivo assays\",\n      \"pmids\": [\"37348029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron/recognition motif on SMARCC2 not mapped\", \"Signals controlling FBXO28 activity unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed disease-associated N-terminal missense variants reduce SMARCC2 expression and disrupt BAF subunit interactions, clarifying a loss-of-function disease mechanism.\",\n      \"evidence\": \"In vitro expression assays, 3D modeling, co-IP, and proximity-ligation assays\",\n      \"pmids\": [\"37551667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional remodeling consequences in neurons not assayed\", \"Which specific subunit contacts are lost not fully enumerated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the degradation paradigm: TRIM37-mediated SMARCC2 turnover activates Wnt signaling and drives sunitinib resistance in renal cell carcinoma.\",\n      \"evidence\": \"Co-IP, western blot of SMARCC2 upon TRIM37 manipulation, and drug-sensitivity/colony/sphere assays\",\n      \"pmids\": [\"39349442\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct ubiquitination of SMARCC2 by TRIM37 not demonstrated\", \"Single Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized SMARCC2's enhancer-accessibility role to oncogenic loci, linking it to PIK3CB enhancer activity and Ras-PI3K signaling in breast cancer stemness.\",\n      \"evidence\": \"siRNA/shRNA knockdown, RNA-seq, ATAC-seq, ChIP, mammosphere assays, and xenografts\",\n      \"pmids\": [\"38852505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SMARCC2 at the PIK3CB enhancer versus complex-mediated effect not separated\", \"Context-dependence across tumor types unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SMARCC2 to histone acetylation control at synaptic genes via HDAC2 binding, mechanistically linking its loss to synaptic and memory deficits reversible by HDAC inhibition.\",\n      \"evidence\": \"Co-IP, ChIP-seq, RNA-seq, H3K9ac ChIP, electrophysiology, behavior, and romidepsin rescue (preprint)\",\n      \"pmids\": [\"40492195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Whether SMARCC2 directly recruits HDAC2 to synaptic promoters versus indirect effect unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMARCC2's biochemical remodeling activity, PTM regulation, and degradation are integrated to select specific enhancers/promoters across distinct tissues remains unresolved.\",\n      \"evidence\": \"No single study reconstitutes SMARCC2-directed remodeling with defined targets across contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SMARCC2 within an assembled BAF complex on chromatin\", \"Modified residues and degrons not mapped\", \"Rules governing tissue-specific target selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 9]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8]}\n    ],\n    \"complexes\": [\"BAF (SWI/SNF) complex\"],\n    \"partners\": [\"SMARCC1\", \"SMARCE1\", \"SIRT6\", \"FBXO28\", \"TRIM37\", \"HDAC2\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}