Affinage

INTS6

Integrator complex subunit 6 · UniProt Q9UL03

Length
887 aa
Mass
100.4 kDa
Annotated
2026-06-10
25 papers in source corpus 16 papers cited in narrative 16 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

INTS6 is a subunit of the Integrator complex that couples RNA polymerase II transcriptional control to genome maintenance by directing the PP2A phosphatase module to chromatin (PMID:39445827, PMID:37995689). Crystallographic and biochemical analysis shows that INTS6 binds INTS3, with two INTS3 protomers dimerizing to engage INTS6 through conserved residues required for double-strand break (DSB) repair (PMID:34400606). At DSBs, INTS6 joins the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric assembly, binds DNA:RNA hybrids, promotes PP2A-mediated dephosphorylation of RNAPII, prevents accumulation of damage-associated RNA transcripts, and recruits senataxin to resolve R-loops (PMID:39445827). The same PP2A-tuning activity governs Integrator-dependent transcription: INTS6 behaves analogously to a PP2A regulatory B subunit, and its overexpression titrates PP2A to modulate premature transcription termination at a subset of protein-coding genes (PMID:37995689). Through these effects on RNAPII dynamics, INTS6 controls early neurogenesis, cortical lamination, and synaptic development, with the underlying RNAPII hyperphosphorylation and overproliferation phenotypes reversible by CDK9 inhibition (PMID:40966122), and it acts upstream of the BMP/Nodal/Wnt8a axis in vertebrate dorsoventral patterning (PMID:24204286). INTS6 additionally functions as a frequently silenced tumor suppressor: its re-expression induces G1 arrest and suppresses colony formation across prostate, lung, colorectal, and liver cancer models, in part by upregulating Wnt-pathway inhibitors and downregulating cyclin D1 (PMID:19906297, PMID:29895194, PMID:15254679), while its promoter is hypermethylated and its transcript is repressed by EBV miR-BART3* and oncomiR-17-5p in various malignancies (PMID:16007164, PMID:23280823, PMID:25686840).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Established the first functional handle on the gene by showing its product is nuclear and antagonizes growth-factor mitogenic signaling, framing it as a candidate growth suppressor.

    Evidence Antibody immunofluorescence and IGF-1 mitogenic response assay after overexpression

    PMID:9473344

    Open questions at the time
    • No molecular mechanism linking the protein to IGF-1R signaling
    • No link to transcription or the Integrator complex yet
  2. 2001 Medium

    Defined the gene structure and a DEAD-box/helicase superfamily II motif and nuclear localization, while implicating promoter CpG hypermethylation in its silencing in tumors.

    Evidence GFP-fusion live imaging, genomic structure determination, bisulfite methylation analysis

    PMID:11939413

    Open questions at the time
    • Predicted helicase activity never demonstrated biochemically
    • Did not establish a transcriptional or DSB function
  3. 2005 Medium

    Showed that promoter hypermethylation causally silences the gene in prostate cancer, since demethylation restores expression, supporting an epigenetically inactivated tumor suppressor.

    Evidence Bisulfite sequencing, promoter luciferase assays, 5-azacytidine demethylation in DU145/LNCaP cells

    PMID:16007164

    Open questions at the time
    • Did not define the downstream effector pathway of suppression
    • Limited primary-tumor sample number
  4. 2006 Medium

    Revealed an unexpected mitochondrial role in the worm ortholog, where loss disrupts inner-membrane topology and triggers apoptosis, raising the question of whether the gene's function is nuclear or organellar.

    Evidence RNAi, immunofluorescence, cryo-EM, ced-3 epistasis in C. elegans

    PMID:16914495

    Open questions at the time
    • Mitochondrial localization not confirmed for the mammalian protein
    • Relationship between mitochondrial and later nuclear/transcriptional roles unresolved
  5. 2009 Medium

    Connected the suppressor activity to a defined cellular program—G1 arrest with Wnt-inhibitor upregulation and cyclin D1 loss—providing the first pathway-level mechanism.

    Evidence Ectopic expression, cell cycle flow cytometry, colony formation, microarray profiling in PC3/DU145

    PMID:19906297

    Open questions at the time
    • Correlative expression changes, not shown to be direct targets
    • Did not link Wnt regulation to a transcription-termination mechanism
  6. 2013 High

    Demonstrated that the gene is targeted for repression by viral and cellular regulators and that it operates upstream of a developmental signaling axis, broadening its biological reach.

    Evidence EBV miR-BART3* 3'-UTR reporter assays in nasopharyngeal carcinoma; zebrafish maternal-effect mutant epistasis on BMP/Nodal/Wnt8a

    PMID:23280823 PMID:24204286

    Open questions at the time
    • Mechanism by which the gene controls the BMP/Nodal/Wnt8a axis not defined
    • Whether developmental and tumor-suppressor functions share a mechanism unknown
  7. 2014 Medium

    Defined a ceRNA circuit in which a pseudogene protects the transcript from oncomiR-17-5p, adding a post-transcriptional layer to tumor suppression in liver cancer.

    Evidence Luciferase miRNA-target assays, overexpression/knockdown, xenografts in HCC

    PMID:25686840

    Open questions at the time
    • Does not connect transcript regulation to protein-level mechanism
    • ceRNA stoichiometry in vivo not quantified
  8. 2018 Medium

    Pinned tumor suppression mechanistically on Wnt/β-catenin, since blocking β-catenin degradation reverses the growth-suppressive effect.

    Evidence Small activating RNA, proliferation/motility assays, β-catenin pathway Western blots and rescue in CRPC cells

    PMID:29895194

    Open questions at the time
    • Direct molecular link between the protein and β-catenin stability not shown
    • Single cancer context
  9. 2021 High

    Reframed the gene's biochemistry by solving the INTS3/INTS6 structure, establishing it as an Integrator subunit whose INTS3-dimer interface is required for DSB repair.

    Evidence 2.4 Å crystal structure, pulldowns, mutagenesis, DSB repair assays; plus colorectal cancer loss/gain-of-function with PI3K/AKT-MAPK epistasis

    PMID:34400606 PMID:34508742

    Open questions at the time
    • Structure did not show how PP2A is engaged
    • Reconciliation of helicase-motif annotation with structural role unaddressed
  10. 2023 High

    Identified the gene as a PP2A-regulatory-B-subunit-like factor that tunes Integrator-dependent transcription termination at select protein-coding genes by titrating PP2A.

    Evidence Drosophila overexpression, RNA-seq, PP2A interaction assays, epistasis with canonical PP2A B subunits

    PMID:37995689

    Open questions at the time
    • Gene-selectivity determinants of which loci are affected not defined
    • Direct structural basis of PP2A engagement not resolved
  11. 2024 High

    Unified the DSB and transcription roles, showing the protein assembles into tetrameric SOSS1, binds DNA:RNA hybrids, drives PP2A-mediated RNAPII dephosphorylation, and recruits senataxin to clear R-loops at breaks.

    Evidence Reciprocal Co-IP, DNA:RNA hybrid binding, proximity ligation, RNAPII phosphorylation and DSB repair assays; plus C. elegans DNA-damage-response RAD-51/CDK-1 data

    PMID:39445827 PMID:39575199

    Open questions at the time
    • Stoichiometry of PP2A handoff between SOSS1 and chromatin not resolved
    • C. elegans DDR finding is single-method per endpoint and not independently confirmed
  12. 2025 High

    Demonstrated a physiological requirement in mammalian brain development, where loss disrupts neurogenesis and synaptic gene transcription via altered RNAPII dynamics, rescuable by CDK9 inhibition.

    Evidence Conditional KO mouse, IHC, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue, behavior

    PMID:40966122

    Open questions at the time
    • Which synaptic-gene targets are directly Integrator-controlled not fully defined
    • Link between neurodevelopmental phenotype and human disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How INTS6's PP2A-recruitment scaffold integrates its DSB-repair, transcription-termination, developmental, and tumor-suppressor activities into a single mechanistic framework remains unresolved.
  • No structure of the INTS6-PP2A-RNAPII assembly
  • Whether Wnt and IGF-1 tumor-suppressor effects are direct consequences of Integrator/PP2A activity is unknown
  • No human disease mutation directly tied to INTS6 in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
HSSB1INIPINTS3PP2ASETX
Complex memberships
Integrator complexSOSS1 complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Crystal structure of the INTS3/INTS6 complex revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues; INTS3 dimerization is required for recognizing longer ssDNA, and perturbation of INTS3c dimerization or disruption of the INTS3c/INTS6c interaction impairs DSB repair. X-ray crystallography (2.4 Å resolution), biochemical pulldown assays, site-directed mutagenesis, DSB repair functional assays Cell discovery High 34400606
2024 INTS6 associates with the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric SOSS1 complex; INTS6 binds DNA:RNA hybrids, promotes PP2A recruitment to DSBs facilitating RNAPII dephosphorylation, prevents accumulation of damage-associated RNA transcripts (DARTs), and interacts with and promotes senataxin (SETX) recruitment to resolve R-loops at DSBs. Co-immunoprecipitation, biochemical binding assays (DNA:RNA hybrid binding), proximity ligation, functional DSB repair assays, RNAPII phosphorylation analysis Nucleic acids research High 39445827
2023 IntS6 (Integrator subunit 6) over-expression in Drosophila blocks Integrator function at a subset of protein-coding genes (but not snRNAs or other attenuated loci) by titrating PP2A subunits; IntS6 functions analogously to a PP2A regulatory B subunit to modulate transcription termination efficiency at select gene loci. Genetic over-expression in Drosophila, RNA-seq, PP2A subunit interaction assays, epistasis with canonical PP2A B subunits Molecular cell High 37995689
2025 INTS6 deficiency in a conditional mouse KO model disrupts early neurogenesis, cortical lamination, and synaptic development; INTS6 loss alters RNAPII dynamics and disrupts transcriptional regulation of synaptic genes. CDK9 inhibition reduced RNAPII phosphorylation and rescued the neurosphere overproliferation and abnormal dendritic spine phenotype caused by Ints6 deficiency. Conditional KO mouse model, behavioral assays, immunohistochemistry, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue experiments The Journal of clinical investigation High 40966122
2013 In zebrafish, maternal-effect loss of Ints6 causes de-repression of dorsal organizer genes, failure to maintain BMP ligand expression, failure to fully express vox and ved (Wnt8a mediators), and severe dorsalization with multiple axial domains and ectopic dorsal forerunner cells; restoring BMP signaling or limiting Nodal signaling rescues wild-type patterning, placing Ints6 upstream of the BMP/Nodal/Wnt8a axis in dorsoventral patterning. Forward genetic screen, maternal-effect recessive mutation analysis, epistasis (BMP/Nodal pathway rescue), in situ hybridization, zebrafish embryology PLoS genetics High 24204286
2001 DICE1 (INTS6) encodes a protein with a DEAD box motif characteristic of ATP-dependent helicases and contains helicase superfamily II motifs; GFP-fusion experiments showed preferential nuclear localization of the DICE1 protein, and CpG sites flanking a predicted TATA box are hypermethylated in tumor cells with decreased DICE1 expression. GFP-fusion protein live imaging, genomic structure determination, bisulfite sequencing/methylation analysis Oncology research Medium 11939413
1998 DBI-1 (INTS6/DICE1) protein localizes to the nucleus and overexpression of DBI-1 in cells containing the wild-type IGF-1 receptor diminishes the mitogenic response to IGF-1. Antibody localization (immunofluorescence), overexpression with IGF-1 mitogenic response assay (thymidine incorporation or growth assay) Experimental cell research Medium 9473344
2004 Ectopic expression of DICE1 cDNA (as GFP fusion) inhibits colony formation of human NSCLC cell lines (SK-MES-1, NCI-H520) and prostate carcinoma (DU145), and suppresses growth in soft agar of IGF-IR-transformed Balb/c 3T3 cells, demonstrating growth-suppressive activity that interferes with anchorage-independent growth dependent on IGF-I signaling. Stable transfection, colony formation assay, soft-agar anchorage-independent growth assay Oncology reports Medium 15254679
2009 Exogenous re-expression of INTS6/DICE1 in androgen-independent PC3 and DU145 prostate cancer cells suppresses colony formation and causes G1 phase cell cycle arrest (not immediate apoptosis); expression profiling revealed upregulation of Wnt pathway inhibitors (CXXC4, FZD7, TCF7L1) and downregulation of cyclin D1, linking INTS6 function to Wnt signaling and cell cycle regulation. Ectopic cDNA expression, colony formation assay, flow cytometry cell cycle analysis, gene expression profiling (microarray) Cancer cell international Medium 19906297
2005 Reduced DICE1 (INTS6) expression in prostate cancer cell lines DU145 and LNCaP is associated with hypermethylation of the DICE1 promoter; treatment with the demethylating agent 5-azacytidine restores DICE1 expression, and hypermethylation of DICE1 CpG promoter sites was observed in 4/8 prostate cancers. Bisulfite sequencing, promoter activity luciferase assay, 5-azacytidine demethylation treatment, RT-PCR Oncogene Medium 16007164
2006 C. elegans DIC-1 (DICE1/INTS6 homolog) localizes to the inner mitochondrial membrane as cytoplasmic foci, and its RNAi knockdown causes abnormal mitochondrial morphology with internal vesicles, increased ced-3-dependent apoptosis in the germline, and embryonic lethality, demonstrating an essential role in mitochondrial inner membrane/cristae topology. RNA interference, immunofluorescence microscopy, cryoelectron microscopy, genetic epistasis (ced-3 dependence) Development (Cambridge, England) Medium 16914495
2018 Small RNA-induced upregulation of INTS6 in castration-resistant prostate cancer cells suppresses cell proliferation and motility, and this effect is associated with downregulation of Wnt/β-catenin signaling; impairment of β-catenin degradation reverses the tumor suppressive effects of INTS6. Small activating RNA transfection, cell proliferation and motility assays, Western blot for β-catenin pathway components, rescue by β-catenin degradation inhibitor Cell cycle (Georgetown, Tex.) Medium 29895194
2021 Downregulation of INTS6 in colorectal cancer cells induces G1/S-phase cell cycle arrest and suppresses growth, while overexpression promotes growth; mechanistically, INTS6 increases levels of phosphorylated AKT (p-AKT) and ERK (p-ERK), and the growth-promoting effect is blocked by AKT and ERK inhibitors; INTS6 also affects c-Myc and CDK2 expression downstream of PI3K/AKT and MAPK signaling. siRNA knockdown, overexpression, flow cytometry, Western blot (p-AKT, p-ERK, c-Myc, CDK2), kinase inhibitor treatment, xenograft tumor assay Experimental cell research Medium 34508742
2013 DICE1 (INTS6) is a cellular target of EBV-encoded miR-BART3* miRNA in nasopharyngeal carcinoma; miR-BART3* targets the 3'-UTR of DICE1 mRNA and down-regulates endogenous DICE1 protein; inhibition of miR-BART3* increases DICE1 protein expression; miR-BART3* expression overcomes the growth-suppressive activity of DICE1. 3'-UTR luciferase reporter assay, anti-miRNA oligonucleotide inhibition, Western blot, colony formation assay International journal of cancer Medium 23280823
2015 INTS6 and its pseudogene INTS6P1 compete for binding of oncomiR-17-5p; INTS6P1 acts as a competing endogenous RNA (ceRNA) to protect INTS6 mRNA from miR-17-5p-mediated repression, and both INTS6 and INTS6P1 exert tumor-suppressive roles in hepatocellular carcinoma through this regulatory circuit. Luciferase reporter assay (miRNA target site), overexpression and knockdown functional assays (growth curves, cell death, migration, in vivo xenograft), microarray expression analysis Oncotarget Medium 25686840
2024 In C. elegans, INTS-6 is necessary for RAD-51 foci formation after X-ray radiation, and CDK-1 Tyr-15 phosphorylation depends on the presence of INTS-6, demonstrating a role for INTS-6 in the DNA damage response. RNAi knockdown, immunofluorescence (RAD-51 foci), Western blot (CDK-1 pY15), X-ray irradiation microPublication biology Low 39575199

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma. International journal of cancer 92 23280823
2015 Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma. Oncotarget 60 25686840
1999 Isolation of DICE1: a gene frequently affected by LOH and downregulated in lung carcinomas. Oncogene 56 10467397
2013 The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis. PLoS genetics 43 24204286
2009 INTS6/DICE1 inhibits growth of human androgen-independent prostate cancer cells by altering the cell cycle profile and Wnt signaling. Cancer cell international 36 19906297
2005 Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer. Oncogene 30 16007164
2001 Molecular characterization of the DICE1 (DDX26) tumor suppressor gene in lung carcinoma cells. Oncology research 30 11939413
2022 Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 Inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells. Molecular cancer therapeutics 25 35247917
2021 Crystal structure of the INTS3/INTS6 complex reveals the functional importance of INTS3 dimerization in DSB repair. Cell discovery 22 34400606
2006 Deleted in cancer 1 (DICE1) is an essential protein controlling the topology of the inner mitochondrial membrane in C. elegans. Development (Cambridge, England) 19 16914495
2004 Ectopic expression of DICE1 suppresses tumor cell growth. Oncology reports 15 15254679
2023 IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events. Molecular cell 13 37995689
2021 INTS6 promotes colorectal cancer progression by activating of AKT and ERK signaling. Experimental cell research 12 34508742
2018 Small RNA-induced INTS6 gene up-regulation suppresses castration-resistant prostate cancer cells by regulating β-catenin signaling. Cell cycle (Georgetown, Tex.) 11 29895194
2005 GABA and glutamate receptors in the horizontal limb of diagonal band of Broca (hDB): effects on cardiovascular regulation. Experimental brain research 11 16034575
1998 DBI-1, a novel gene related to the notch family, modulates mitogenic response to insulin-like growth factor 1. Experimental cell research 10 9473344
1999 Analysis of the mouse MAP1B gene identifies a highly conserved 4.3 kb 3' untranslated region and provides evidence against the proposed structure of DBI-1 cDNA. Biochimica et biophysica acta 8 10366719
2024 Tetrameric INTS6-SOSS1 complex facilitates DNA:RNA hybrid autoregulation at double-strand breaks. Nucleic acids research 7 39445827
2019 A second HD mating type sublocus of Flammulina velutipes is at least di-allelic and active: new primers for identification of HD-a and HD-b subloci. PeerJ 6 30809430
2005 Interaction of GABA and glutamate in the horizontal limb of diagonal band of Broca (hDB): role in cardiovascular responses. Brain research 6 15823251
2023 Skin Barrier-Enhancing Effects of Dermabiotics HDB with Regulation of Skin Microbiota. Journal of microbiology and biotechnology 3 37915264
2015 Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14. Urologia internationalis 3 25660097
2025 Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development. The Journal of clinical investigation 1 40966122
2026 Genome characterization and comparative genomics of Limosilactobacillus reuteri HDB isolated from the gut of an Indian infant. Frontiers in microbiology 0 42078525
2024 Integrator complex subunit 6 (INTS-6) mediates DNA damage response in Caenorhabditis elegans. microPublication biology 0 39575199

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