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SIN3B

Paired amphipathic helix protein Sin3b · UniProt O75182

Length
1162 aa
Mass
133.1 kDa
Annotated
2026-04-28
31 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIN3B is a scaffold protein that nucleates HDAC-containing co-repressor complexes to silence gene expression, enforce quiescence, and promote cellular senescence and differentiation. Cryo-EM reveals that SIN3B encircles HDAC, contacts its allosteric basic patch to stimulate deacetylase catalysis, and inserts a loop into the catalytic tunnel to guide substrate lysine selection (PMID:37137925). Through its PAH domains, SIN3B recruits diverse transcription factors—including Mad1, p53, E2Fs (via the DREAM complex), Myc, MNF-β, and RFX5—to target promoters, where it establishes repressive chromatin marked by histone deacetylation and H3K9 methylation (PMID:11101889, PMID:30517867, PMID:22028823, PMID:24709079). SIN3B haploinsufficiency in humans causes a syndromic intellectual disability/autism spectrum disorder associated with enhancer and promoter hyperacetylation (PMID:33811806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 High

    Determination of how SIN3B physically engages transcription factor partners resolved the molecular basis of co-repressor recruitment: the PAH2 domain forms a wedged helical bundle whose hydrophobic cleft docks an amphipathic helix from Mad1, and a parallel study showed MNF-β requires SIN3B binding for transcriptional repression and growth inhibition.

    Evidence NMR solution structure of PAH2–Mad1 complex; Co-IP, mutagenesis, and transcription/growth assays for MNF-β–SIN3B

    PMID:10620510 PMID:11101889

    Open questions at the time
    • Whether different PAH domains (PAH1–4) engage distinct partner classes was not resolved
    • Stoichiometry of full holo-complex unknown at this stage
  2. 2008 Medium

    The finding that SIN3B interacts with ETO homologues and co-localizes in the nucleolus expanded the repertoire of SIN3B-recruiting factors beyond classical Mad/Max repressors and suggested roles at nucleolar loci.

    Evidence Co-IP of endogenous proteins and immunofluorescence co-localization in K562 cells

    PMID:18205948

    Open questions at the time
    • Functional consequence of nucleolar SIN3B–ETO interaction on gene expression not established
    • No reciprocal loss-of-function experiments
  3. 2009 High

    Genetic loss-of-function experiments established that SIN3B is required for both replicative and oncogene-induced senescence, positioning SIN3B as a critical effector of the senescence tumor-suppression barrier.

    Evidence Sin3B-null primary fibroblasts refractory to senescence; overexpression triggers senescence-associated heterochromatic foci

    PMID:19654306

    Open questions at the time
    • Target genes through which SIN3B enforces senescence not identified at this stage
    • Mechanism linking HDAC activity to heterochromatic foci formation unresolved
  4. 2010 High

    Identification of a SIN3B–HDAC1–Mrg15–Pf1 complex localized downstream of transcription start sites revealed a distinct function in restoring repressive chromatin within transcribed gene bodies, and RNF220 was identified as the E3 ubiquitin ligase controlling SIN3B turnover via the proteasome.

    Evidence Reciprocal Co-IP and ChIP with shRNA knockdown for the chromatin complex; yeast two-hybrid, Co-IP, and ubiquitination assays for RNF220

    PMID:20170641 PMID:21041482

    Open questions at the time
    • How SIN3B is targeted specifically to gene bodies versus promoters remained unclear
    • Whether RNF220-mediated degradation is signal-regulated was not tested
  5. 2011 Medium

    Direct interaction mapping between p53 and SIN3B, and stress-dependent recruitment of SIN3B to p53 target promoters, established SIN3B as a co-repressor for genotoxic-stress-responsive gene silencing coupled to H3K9 trimethylation.

    Evidence Co-IP with domain mapping, ChIP at p53 target genes upon Adriamycin treatment, histone modification analysis

    PMID:22028823

    Open questions at the time
    • Whether SIN3B represses all or a subset of p53 targets genome-wide not determined
    • Single lab finding, not independently replicated
  6. 2014 Medium

    A series of studies in 2014 placed SIN3B at the intersection of oncogene-induced senescence in vivo, Bmi-1-mediated transcriptional regulation, Myc turnover, and interferon-γ signaling: SIN3B is required for KRAS-induced senescence and IL-1α production in pancreatic cancer; Bmi-1 directly represses the SIN3B locus, linking Polycomb regulation to senescence control; SIN3B–HDAC1 deacetylates Myc to promote its proteasomal degradation; and SIN3B cooperates with G9a downstream of RFX5 to repress COL1A2 upon IFN-γ stimulation.

    Evidence Genetic mouse models (pancreatic cancer, Bmi-1 ChIP), yeast two-hybrid/PLA/ChIP for Myc interaction, ChIP/Co-IP/shRNA for RFX5–SIN3B–G9a axis

    PMID:24691445 PMID:24709079 PMID:24951594 PMID:25263442

    Open questions at the time
    • Each study from a single lab; independent replication pending
    • How SIN3B selects among its diverse transcription-factor partners in different signaling contexts remains unresolved
    • Whether Myc deacetylation by SIN3B–HDAC1 is a general mechanism or cell-type-specific not tested
  7. 2016 Medium

    Conditional knockout of Sin3B in hematopoietic stem cells demonstrated its requirement for HSC quiescence, competitive repopulation, and differentiation; separately, RBM39-dependent alternative splicing of SIN3B was shown to produce functionally distinct isoforms that differentially recruit HDACs to regulate BMP4-responsive transcription.

    Evidence Hematopoietic-specific conditional KO with transplantation assays; siRNA screen, RNA-seq, and isoform-specific knockdown for splicing study

    PMID:27324164 PMID:27806947

    Open questions at the time
    • Target genes through which SIN3B maintains HSC quiescence not identified
    • Whether the alternative splicing mechanism operates in tissues beyond the BMP4 reporter context is unknown
  8. 2017 Medium

    In vivo evidence that SIN3B loss permits progression from PTEN-loss-induced senescence to invasive prostate adenocarcinoma established SIN3B as a bona fide tumor-suppressive barrier acting through senescence.

    Evidence Conditional Sin3B KO in a PTEN-loss prostate cancer mouse model with histopathology

    PMID:28807943

    Open questions at the time
    • Specific chromatin targets mediating the senescence-to-malignancy transition not defined
    • Single in vivo model; generalizability across cancer types not tested
  9. 2018 High

    Unbiased proteomics identified SIN3B as a physical component of the DREAM complex, and genetic epistasis showed SIN3B cooperates with APC/C^CDH1 to enforce quiescence by repressing DREAM target genes, establishing a dual-lock model for cell-cycle exit.

    Evidence Proteomics, genetic inactivation, double-mutant epistasis, gene expression analysis

    PMID:30517867

    Open questions at the time
    • Whether SIN3B is a stoichiometric DREAM subunit or a transient interactor is unresolved
    • Which HDAC(s) within the SIN3B–DREAM axis mediate target gene repression not specified
  10. 2021 Medium

    Human genetic evidence that SIN3B haploinsufficiency causes syndromic intellectual disability/ASD, corroborated by craniofacial and axonal defects in zebrafish and genome-wide enhancer hyperacetylation in patient cells, linked SIN3B's HDAC-dependent chromatin function to neurodevelopment.

    Evidence Patient deletion/SNV identification, zebrafish CRISPR KO, H3K27ac ChIP-seq in patient PBMCs

    PMID:33811806

    Open questions at the time
    • Which SIN3B target genes drive the neurodevelopmental phenotype not identified
    • Whether the hyperacetylation is a direct or indirect consequence of SIN3B loss not fully resolved
  11. 2023 High

    The cryo-EM structure of the complete SIN3B holo-complex resolved the architectural basis of scaffold-mediated HDAC activation: SIN3B encircles HDAC, allosterically stimulates catalysis via a basic-patch contact, and uses a catalytic-tunnel-inserted loop for substrate guidance; separately, SIN3B was found to be rapidly recruited to DNA double-strand breaks where it directs MDC1 accumulation and promotes canonical NHEJ.

    Evidence Cryo-EM with substrate mimic and proteomics; immunofluorescence foci analysis, genetic inactivation, drug sensitivity and repair pathway assays

    PMID:37137925 PMID:37314748

    Open questions at the time
    • Whether the allosteric activation mechanism differs for HDAC1 vs HDAC2 not compared structurally
    • How SIN3B is targeted to DSB sites and whether this requires its HDAC activity is unknown
    • The DNA-repair role has not been independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIN3B selects among its many transcription-factor partners in a context-dependent manner, how its alternative isoforms differentially assemble distinct complexes, and whether its newly described DNA-repair function is mechanistically linked to its chromatin co-repressor activity remain unresolved.
  • No systematic genome-wide map of SIN3B occupancy across cell states integrating isoform identity
  • Structural basis for partner selectivity among PAH domains incompletely resolved
  • Relationship between HDAC scaffold and DNA-damage-response functions not mechanistically connected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 5 GO:0000228 nuclear chromosome 4 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1640170 Cell Cycle 4 R-HSA-1266738 Developmental Biology 1 R-HSA-73894 DNA Repair 1
Partners
HDAC1HDAC2MRG15MYCPHF12RFX5RNF220TP53
Complex memberships
DREAM complexSIN3B-HDAC holo-complexSIN3B-HDAC1-Mrg15-Pf1 complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Cryo-EM structure of the complete human SIN3B histone deacetylase holo-complex reveals that SIN3B encircles the deacetylase HDAC and contacts its allosteric basic patch to stimulate catalysis; a SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilizes the substrate for specific deacetylation guided by a substrate receptor subunit. Cryo-EM structure determination with and without substrate mimic, proteomics (MS) Nature communications High 37137925
2000 NMR solution structure of the PAH2 domain of Sin3B in complex with the N-terminal Mad1 peptide reveals a 'wedged helical bundle' interaction fold: four PAH2 alpha-helices form a hydrophobic cleft that accommodates an amphipathic Mad1 alpha-helix, and Mad1 binding stabilizes secondary structure elements of PAH2. NMR spectroscopy, solution structure determination Nature structural biology High 11101889
2010 Sin3B forms a novel mammalian complex with HDAC1, Mrg15, and PHD finger-containing Pf1 that localizes ~1 kb downstream of the transcription start site of transcribed genes; inactivation of this complex increases RNA polymerase II progression within transcribed regions and elevates transcription, indicating the complex restores repressive chromatin at actively transcribed loci. Co-immunoprecipitation, ChIP, shRNA knockdown, gene expression analysis Molecular and cellular biology High 21041482
2009 Sin3B is required for replicative and oncogene-induced senescence in primary mammalian fibroblasts; Sin3B-null fibroblasts are refractory to senescence, while Sin3B overexpression triggers senescence and formation of senescence-associated heterochromatic foci. Genetic inactivation (Sin3B-/- cells), overexpression, senescence assays (SA-β-gal, BrdU incorporation, SAHF formation) Cancer research High 19654306
2018 Sin3B physically associates with the DREAM complex (identified by unbiased proteomics) and represses DREAM target genes during quiescence; Sin3B-/- cells show de-repression of DREAM targets in quiescence, and combined Sin3B inactivation with APC/CCDH1 inactivation, but not Sin3B inactivation alone, allows quiescent cells to re-enter the cell cycle. Proteomics (unbiased), genetic inactivation, genetic epistasis (double mutant), gene expression analysis Cell reports High 30517867
2010 RNF220, a RING-finger E3 ubiquitin ligase, specifically interacts with Sin3B in vitro and in vivo, promotes Sin3B ubiquitination, and targets it for proteasomal degradation, establishing RNF220 as the E3 ligase that ubiquitinates Sin3B. Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments Biochemical and biophysical research communications Medium 20170641
2000 MNF-beta (myocyte nuclear factor-beta), a winged-helix/forkhead protein, forms a co-repressor complex with mammalian Sin3B (mSin3B) to repress transcription; MNF-beta mutants that fail to bind mSin3B are defective in transcriptional repression and negative growth regulation. Co-immunoprecipitation, transcriptional repression assays, oncogenic transformation assays, mutagenesis The Biochemical journal Medium 10620510
2011 p53 directly interacts with Sin3B (hSin3B) via amino acids 1–399 of hSin3B binding the N-terminal region (aa 1–108) of p53; upon genotoxic stress (Adriamycin), increased hSin3B is recruited to promoters of p53 target genes (HSPA8, MAD1, CRYZ) in a p53-dependent manner, leading to their repression and increased H3K9 trimethylation. Co-immunoprecipitation, ChIP, shRNA knockdown, domain mapping, histone modification analysis PloS one Medium 22028823
2014 Sin3B interacts with Myc protein in a Max-independent manner in human and rat cell nuclei; Sin3B recruits HDAC1 to Myc complexes, and HDAC1 deacetylase activity mediates Sin3B-induced Myc deacetylation and subsequent proteasomal degradation, lowering Myc protein levels. Yeast two-hybrid, co-immunoprecipitation, proximity ligation assay, immunofluorescence, ChIP, overexpression and knockdown The Journal of biological chemistry Medium 24951594
2014 Bmi-1 directly represses the Sin3B locus; oncogenic stress leads to dissociation of Bmi-1 from the Sin3B promoter, resulting in increased Sin3B expression and entry into senescence. Sin3B is also required for the elevated reactive oxygen species phenotype upon Bmi-1 depletion. ChIP, genetic inactivation, ROS measurement, senescence assays Oncogene Medium 25263442
2014 Sin3B is required for activated KRAS-induced senescence in vivo in a mouse model of pancreatic cancer; Sin3B inactivation impairs KRAS-induced IL-1α production, and SIN3B levels correlate with IL-1α production in murine and human pancreatic cells. Genetic mouse model (Sin3B knockout), immunohistochemistry, cytokine measurement (ELISA), human tissue analysis The Journal of clinical investigation Medium 24691445
2014 Sin3B mediates IFN-γ-induced repression of COL1A2 in vascular smooth muscle cells by being recruited by RFX5 (via HDAC2-mediated deacetylation of RFX5) to the COL1A2 transcription start site, where it cooperates with G9a to establish repressive chromatin (histone deacetylation and H3K9 methylation). ChIP, shRNA knockdown, histone modification analysis, co-immunoprecipitation Biochemical and biophysical research communications Medium 24709079
2013 Sin3B directly binds voltage-gated sodium (Nav) channels via its N-terminal region (containing two PAH domains), interacting with a 132-residue cytoplasmic C-terminal portion of Nav channels; expression of short Sin3B variant reduces native sodium current and Nav-channel gating charge without affecting channel protein levels, suggesting Sin3B influences Nav-channel trafficking or membrane stability. Yeast two-hybrid screen, pull-down, co-immunoprecipitation, immunofluorescence co-localization, electrophysiology Scientific reports Medium 24077057
2008 hSIN3B interacts with ETO homologues (ETO and MTG16, but not MTGR1) via the amino terminus and NHR2 domain of ETO, forming nucleolar complexes; endogenous hSIN3B and ETO/MTG16 co-localize in the nucleolus of K562 cells and in primary placental nuclear extracts. Co-immunoprecipitation (ectopic and endogenous), nuclear extract pull-down, immunofluorescence co-localization BMC molecular biology Medium 18205948
2016 Hematopoietic-specific genetic inactivation of Sin3B severely impairs competitive repopulation capacity of hematopoietic stem cells (HSCs), causes HSC accumulation with failure to differentiate, impairs HSC quiescence, and sensitizes mice to myelosuppressive therapy, identifying Sin3B as a critical regulator of HSC function. Conditional genetic knockout (hematopoietic-specific), bone marrow transplantation, flow cytometry, quiescence assays Blood Medium 27806947
2017 SIN3B is required for PTEN-loss-induced cellular senescence in a mouse prostate cancer model; SIN3B inactivation permits progression to invasive prostate adenocarcinoma, indicating SIN3B acts as a barrier to malignant progression through senescence induction. Genetic mouse model (Sin3B conditional KO), histopathology, gene expression analysis Cancer research Medium 28807943
2016 RBM39-dependent alternative splicing of SIN3B produces long and short isoforms; BMP4 stimulation shifts expression to the long isoform that recruits HDACs to chromatin to repress transcription, whereas RBM39 knockdown prevents this isoform shift, enhancing BMP4-dependent transcription. Knockdown of the long isoform alone enhances BMP4 transcription. siRNA screen, RNA-seq (transcriptome-wide), isoform-specific knockdown, BMP-responsive luciferase reporter Scientific reports Medium 27324164
2023 SIN3B is rapidly recruited to DNA double-strand break sites where it directs accumulation of MDC1 (Mediator of DNA Damage Checkpoint 1); SIN3B inactivation delays DSB resolution, sensitizes cancer cells to cisplatin and doxorubicin, and favors alternative NHEJ over canonical NHEJ. Immunofluorescence (foci), genetic inactivation, drug sensitivity assays, DNA repair pathway analysis Molecular cancer research : MCR Medium 37314748
2021 SIN3B haploinsufficiency in humans causes a syndromic intellectual disability/autism spectrum disorder; SIN3B disruption in zebrafish causes craniofacial patterning defects and commissural axon defects; H3K27ac ChIP-seq in patient PBMCs shows SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters, consistent with loss of HDAC-mediated deacetylation. Human genetics (deletion/SNV identification), zebrafish CRISPR-Cas9 knockout, H3K27ac ChIP-seq American journal of human genetics Medium 33811806
2025 Structural comparison of SIN3B/HDAC2 with MTA1/HDAC1 complexes confirms that SIN3B recruits HDAC through a distinct surface that does not involve the Y48 residue contacted by ELM2/SANT domain-containing proteins; a single HDAC1 mutation (Y48E) disrupts binding to all complexes except SIN3, demonstrating the differential molecular mode of HDAC recruitment by SIN3B versus other HDAC complexes. Structural comparison (existing structures), co-immunoprecipitation with HDAC1 surface mutants, mass spectrometry bioRxivpreprint Medium bio_10.1101_2025.02.24.639909

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression. The Journal of clinical investigation 66 24691445
2010 A novel mammalian complex containing Sin3B mitigates histone acetylation and RNA polymerase II progression within transcribed loci. Molecular and cellular biology 66 21041482
2000 The winged-helix/forkhead protein myocyte nuclear factor beta (MNF-beta) forms a co-repressor complex with mammalian sin3B. The Biochemical journal 62 10620510
2000 The Mad1-Sin3B interaction involves a novel helical fold. Nature structural biology 52 11101889
2009 Sin3B expression is required for cellular senescence and is up-regulated upon oncogenic stress. Cancer research 49 19654306
2010 RNF220, an E3 ubiquitin ligase that targets Sin3B for ubiquitination. Biochemical and biophysical research communications 39 20170641
2016 SIN3A and SIN3B differentially regulate breast cancer metastasis. Oncotarget 34 27780928
2011 Tumor suppressor protein p53 recruits human Sin3B/HDAC1 complex for down-regulation of its target promoters in response to genotoxic stress. PloS one 32 22028823
2018 The HDAC-Associated Sin3B Protein Represses DREAM Complex Targets and Cooperates with APC/C to Promote Quiescence. Cell reports 30 30517867
2014 Sin3b interacts with Myc and decreases Myc levels. The Journal of biological chemistry 26 24951594
2021 Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder. American journal of human genetics 24 33811806
2014 Sin3B mediates collagen type I gene repression by interferon gamma in vascular smooth muscle cells. Biochemical and biophysical research communications 23 24709079
2008 Sin3B: an essential regulator of chromatin modifications at E2F target promoters during cell cycle withdrawal. Cell cycle (Georgetown, Tex.) 23 18469515
2023 Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex. Nature communications 20 37137925
2014 Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation. Oncogene 18 25263442
2019 SIN3B promotes integrin αV subunit gene transcription and cell migration of hepatocellular carcinoma. Journal of molecular cell biology 17 30215728
2016 The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice. Blood 15 27806947
2017 Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence. Cancer research 11 28807943
2016 Negative autoregulation of BMP dependent transcription by SIN3B splicing reveals a role for RBM39. Scientific reports 11 27324164
2024 SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 39316363
2017 Zebrafish sin3b mutants are viable but have size, skeletal, and locomotor defects. Developmental dynamics : an official publication of the American Association of Anatomists 10 28850761
2017 The potential of targeting Sin3B and its associated complexes for cancer therapy. Expert opinion on therapeutic targets 9 28956957
2013 Interaction between the transcriptional corepressor Sin3B and voltage-gated sodium channels modulates functional channel expression. Scientific reports 9 24077057
2008 The human SIN3B corepressor forms a nucleolar complex with leukemia-associated ETO homologues. BMC molecular biology 6 18205948
2014 SIN3B, the SASP, and pancreatic cancer. Molecular & cellular oncology 5 27308374
2015 pH might play a role in regulating the function of paired amphipathic helices domains of human Sin3B by altering structure and thermodynamic stability. Biochemistry. Biokhimiia 3 25869359
2015 Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes. Bioscience reports 3 26181367
2024 Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells. Epigenetics & chromatin 2 38254205
2023 The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation. bioRxiv : the preprint server for biology 1 36747851
2023 Chromatin-Associated SIN3B Protects Cancer Cells from Genotoxic Stress-Induced Apoptosis and Dictates DNA Damage Repair Pathway Choice. Molecular cancer research : MCR 1 37314748
2025 Knockout of SIN3B modulates transcriptional programs and cell survival in cutaneous melanoma. Pharmacological research 0 40393534