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SMARCC2

SWI/SNF complex subunit SMARCC2 · UniProt Q8TAQ2

Length
1214 aa
Mass
132.9 kDa
Annotated
2026-06-10
20 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    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

    PMID:16199878

    Open questions at the time
    • Does not define the assembled BAF architecture in vivo
    • Mechanism by which excess BAF57 is selected for degradation not resolved
  2. 2015 Medium

    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

    PMID:26121422

    Open questions at the time
    • Direct chromatin targets mediating the reprogramming block not identified
    • Whether the effect requires BAF complex integrity untested
  3. 2016 Medium

    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

    PMID:27392482

    Open questions at the time
    • Molecular targets driving progenitor maintenance not defined
    • Chromatin remodeling activity not directly linked to the phenotype
  4. 2018 Low

    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

    PMID:30580808

    Open questions at the time
    • Indirect domain inference without direct in vitro domain assays
    • Variant effect on remodeling activity not measured
  5. 2019 High

    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

    PMID:31216030

    Open questions at the time
    • Modified residue(s) on SMARCC2 not mapped
    • Generality beyond HO-1/NRF2 loci unknown
  6. 2021 Low

    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

    PMID:34080022

    Open questions at the time
    • No reciprocal validation of the interaction
    • How SMARCC2 represses c-Myc not mechanistically resolved
  7. 2022 Medium

    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

    PMID:36418306

    Open questions at the time
    • Whether DKK1 regulation requires intact BAF complex not shown
    • Direct biochemical SWIRM activity not reconstituted
  8. 2023 Medium

    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

    PMID:37348029

    Open questions at the time
    • Degron/recognition motif on SMARCC2 not mapped
    • Signals controlling FBXO28 activity unknown
  9. 2023 Medium

    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

    PMID:37551667

    Open questions at the time
    • Functional remodeling consequences in neurons not assayed
    • Which specific subunit contacts are lost not fully enumerated
  10. 2024 Low

    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

    PMID:39349442

    Open questions at the time
    • Direct ubiquitination of SMARCC2 by TRIM37 not demonstrated
    • Single Co-IP without reciprocal validation
  11. 2024 Medium

    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

    PMID:38852505

    Open questions at the time
    • Direct binding of SMARCC2 at the PIK3CB enhancer versus complex-mediated effect not separated
    • Context-dependence across tumor types unclear
  12. 2025 Medium

    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)

    PMID:40492195

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Whether SMARCC2 directly recruits HDAC2 to synaptic promoters versus indirect effect unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SMARCC2's biochemical remodeling activity, PTM regulation, and degradation are integrated to select specific enhancers/promoters across distinct tissues remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Complex memberships
BAF (SWI/SNF) complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 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. Exogenous expression of wild-type and deletion mutants, proteasome inhibitor assays, domain-mapping co-immunoprecipitation Molecular and cellular biology Medium 16199878
2019 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. SIRT6 separation-of-function mutants, in vitro mono-ADP-ribosylation assay, ChIP, chromatin conformation capture (3C/loop analysis), siRNA knockdown Nucleic acids research High 31216030
2016 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. Conditional knockout mouse model, Morris water maze behavioral testing, histological analysis of neural progenitor cell populations Molecular neurobiology Medium 27392482
2015 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. shRNA-mediated knockdown in mouse reprogramming assay, iPSC colony counting, pre-iPSC reprogramming assay, Jak/Stat3 inhibitor treatment Stem cells and development Medium 26121422
2021 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. Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression, wound-healing assay, Transwell invasion assay, Western blotting Molecular medicine reports Low 34080022
2022 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. 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 Cell death & disease Medium 36418306
2023 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. 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 Aging Medium 37348029
2024 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. Co-immunoprecipitation to identify TRIM37-SMARCC2 interaction, western blot for SMARCC2 protein levels upon TRIM37 manipulation, functional assays (colony formation, sphere formation, drug sensitivity) Cell death discovery Low 39349442
2024 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. SMARCC2 siRNA/shRNA knockdown, RNA-seq, ATAC-seq for chromatin accessibility, ChIP analysis, cell proliferation and mammosphere assays, xenograft model Biochemical and biophysical research communications Medium 38852505
2025 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. 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 bioRxivpreprint Medium 40492195
2018 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. Whole-exome sequencing of 15 affected individuals, genotype-phenotype correlation, domain mapping American journal of human genetics Low 30580808
2023 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. In vitro protein expression assays, 3D protein modeling, co-immunoprecipitation, proximity-ligation assays Genetics in medicine Medium 37551667

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Regulating SWI/SNF subunit levels via protein-protein interactions and proteasomal degradation: BAF155 and BAF170 limit expression of BAF57. Molecular and cellular biology 106 16199878
2018 Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay. American journal of human genetics 76 30580808
2019 SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic acids research 68 31216030
2016 Ablation of BAF170 in Developing and Postnatal Dentate Gyrus Affects Neural Stem Cell Proliferation, Differentiation, and Learning. Molecular neurobiology 40 27392482
2018 Molecular mechanisms of lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis in gastric cancer. Cancer letters 27 29337109
2019 Plasma long noncoding RNAs PANDAR, FOXD2-AS1, and SMARCC2 as potential novel diagnostic biomarkers for gastric cancer. Cancer management and research 26 31308753
2015 Knockdown of Brm and Baf170, Components of Chromatin Remodeling Complex, Facilitates Reprogramming of Somatic Cells. Stem cells and development 14 26121422
2023 Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals. Genetics in medicine : official journal of the American College of Medical Genetics 12 37551667
2022 SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of glioblastoma. Cell death & disease 9 36418306
2021 SMARCC2 combined with c‑Myc inhibits the migration and invasion of glioma cells via modulation of the Wnt/β‑catenin signaling pathway. Molecular medicine reports 9 34080022
2023 FBXO28 promotes proliferation, invasion, and metastasis of pancreatic cancer cells through regulation of SMARCC2 ubiquitination. Aging 7 37348029
2005 Monoclonal antibodies reactive with the BAF155 (SMARCC1) and BAF170 (SMARCC2) components of human SWI/SNF-related complexes. Hybridoma (2005) 4 15785210
2022 De Novo SMARCC2 Variant in a Chinese Woman with Coffin-Siris Syndrome 8: a Case Report with Mild Intellectual Disability and Endocrinopathy. Journal of molecular neuroscience : MN 3 35536477
2025 Identification and functional analysis of a novel SMARCC2 splicing variant in a family with syndromic neurodevelopmental disorder. Orphanet journal of rare diseases 2 39901255
2024 SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer. Biochemical and biophysical research communications 2 38852505
2024 N6-methyladenosine-modified TRIM37 augments sunitinib resistance by promoting the ubiquitin-degradation of SmARCC2 and activating the Wnt signaling pathway in renal cell carcinoma. Cell death discovery 2 39349442
2026 Clinical and Genetic Analysis of SMARCC2-Related Diseases in Three Chinese Patients. Molecular genetics & genomic medicine 1 41532374
2026 [Clinical characteristics and genetic analysis of a child with Coffin-Siris syndrome type 8 due to an intronic variant of SMARCC2 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 42091196
2025 Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene Smarcc2 and its Rescue by Histone Deacetylase Inhibition. bioRxiv : the preprint server for biology 0 40492195
2025 Long-read sequencing identifies a novel de novo inversion in SMARCC2 in a pediatric patient with Coffin-siris syndrome 8: a case report. BMC medical genomics 0 41291750

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