Affinage

INTS6

Integrator complex subunit 6 · UniProt Q9UL03

Length
887 aa
Mass
100.4 kDa
Annotated
2026-04-28
24 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS6 is a subunit of the Integrator complex that functions at the intersection of RNA polymerase II (RNAPII) transcription control, DNA damage repair, and developmental signaling. Within the Integrator complex, INTS6 recruits the PP2A phosphatase module to regulate RNAPII phosphorylation and premature transcription termination at a subset of protein-coding genes; overexpression titrates PP2A subunits and selectively blocks phosphatase-dependent attenuation without affecting snRNA processing (PMID:37995689). INTS6 also forms a tetrameric complex with the SOSS1 DNA repair machinery (INTS3, INIP, hSSB1) through a structurally defined C-terminal interface with INTS3, enabling recognition of DNA:RNA hybrids, recruitment of senataxin to resolve R-loops at double-strand breaks, and PP2A-mediated RNAPII dephosphorylation at damage sites (PMID:34400606, PMID:39445827). Conditional knockout of Ints6 in the mouse nervous system disrupts neurogenesis, cortical lamination, and synaptic development through dysregulated RNAPII elongation, and these phenotypes are rescued by CDK9 inhibition, establishing INTS6 as a critical regulator of transcription elongation dynamics during brain development (PMID:40966122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 Medium

    Initial characterization established that the INTS6 ortholog (DBI-1) is a nuclear protein capable of modulating growth factor signaling, linking it to cell proliferation control before its Integrator complex membership was known.

    Evidence Immunofluorescence and overexpression/proliferation assays in mouse cells with IGF-1 receptor

    PMID:9473344

    Open questions at the time
    • Mechanism of IGF-1 response modulation unresolved
    • No direct binding partner identified
    • Overexpression-only phenotype without loss-of-function
  2. 2004 Medium

    Growth-suppressive activity of INTS6 was confirmed across multiple cancer cell lines, reinforcing its role as an anti-proliferative factor but leaving the molecular mechanism undefined.

    Evidence Colony formation and soft-agar assays with GFP-DICE1 fusion in lung and prostate carcinoma lines

    PMID:15254679

    Open questions at the time
    • No pathway epistasis performed
    • Overexpression artifact not excluded
    • Endogenous loss-of-function data lacking
  3. 2009 Medium

    Re-expression experiments placed INTS6 upstream of Wnt/β-catenin signaling and cell-cycle progression, providing the first pathway-level explanation for its growth-suppressive phenotype.

    Evidence Colony formation, FACS cell-cycle analysis, and expression profiling in prostate cancer cells

    PMID:19906297

    Open questions at the time
    • Direct physical link to Wnt pathway components not shown
    • Expression profiling correlative
    • No in vivo validation
  4. 2013 High

    Maternal-effect loss of Ints6 in zebrafish demonstrated an essential in vivo role in vertebrate embryonic patterning through BMP/Nodal signaling balance, extending INTS6 function beyond cancer biology to developmental signaling.

    Evidence Maternal-effect mutation in zebrafish with BMP/Nodal genetic epistasis and in situ hybridization

    PMID:24204286

    Open questions at the time
    • Whether Integrator complex integrity is required for the BMP/Nodal phenotype not tested
    • Mechanism connecting INTS6 to BMP ligand transcription unknown
    • Mammalian developmental phenotype not yet examined
  5. 2021 High

    Structural determination of the INTS3–INTS6 C-terminal interface at atomic resolution defined how INTS6 integrates into the SOSS1 DNA repair complex and showed that this interaction is required for double-strand break repair.

    Evidence X-ray crystallography at 2.4 Å, EMSA, site-directed mutagenesis, and DSB repair functional assays

    PMID:34400606

    Open questions at the time
    • Full-length complex structure not available
    • How INTS6 switches between Integrator and SOSS1 functions unknown
    • Contribution of INTS6 to ssDNA recognition versus scaffolding not separated
  6. 2023 High

    Genetic epistasis in Drosophila resolved INTS6's specific role within the Integrator complex: it recruits PP2A phosphatase activity for premature transcription termination at select protein-coding genes but is dispensable for snRNA processing, establishing functional modularity within Integrator.

    Evidence IntS6 overexpression in Drosophila with RNA-seq, ChIP-seq, and epistasis with PP2A B-subunit

    PMID:37995689

    Open questions at the time
    • Endogenous loss-of-function in Drosophila not shown in this study
    • Whether PP2A recruitment is direct or via intermediate subunits not resolved
    • Locus-specificity determinants not identified
  7. 2024 High

    Biochemical reconstitution of the tetrameric SOSS1 complex showed INTS6 directly binds DNA:RNA hybrids, recruits senataxin for R-loop resolution, and promotes PP2A-mediated RNAPII dephosphorylation at DSBs, unifying its transcription and repair functions through a common phosphatase-recruitment mechanism.

    Evidence Co-IP, in vitro binding assays, proximity ligation, and DSB repair functional assays

    PMID:39445827

    Open questions at the time
    • Structural basis of DNA:RNA hybrid recognition by INTS6 unknown
    • Whether senataxin recruitment is direct or via R-loop intermediates not determined
    • Relative contributions of Integrator-associated versus SOSS1-associated INTS6 pools in vivo unclear
  8. 2025 High

    Conditional knockout in mouse brain established INTS6 as essential for neurogenesis and cortical development via RNAPII elongation control, and CDK9 inhibitor rescue demonstrated that the phenotype arises from unrestrained RNAPII phosphorylation, providing the first mammalian in vivo mechanistic link.

    Evidence Nestin-Cre conditional KO mouse, RNAPII ChIP, CDK9 inhibitor rescue, neurosphere assays, behavioral testing

    PMID:40966122

    Open questions at the time
    • Which specific gene targets are dysregulated to cause cortical defects not fully cataloged
    • Whether the CDK9/PP2A axis operates identically in non-neural tissues unknown
    • Human neurodevelopmental disease association from patient mutations not yet reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • How INTS6 is partitioned between Integrator complex and SOSS1 complex functions, what determines locus-specific engagement, and whether INTS6 loss-of-function causes human Mendelian disease remain unresolved.
  • No structural model of full-length INTS6 in the intact Integrator complex
  • Regulatory signals governing INTS6 allocation between Integrator and SOSS1 unknown
  • No human disease-causing mutations reported in the primary literature

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-1266738 Developmental Biology 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
INIPINTS3NABP2PPP2CASETX
Complex memberships
Integrator complexSOSS1 complex (tetrameric form with INTS3/INIP/hSSB1)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Crystal structure of the INTS3 C-terminus in complex with the INTS6 C-terminus (at 2.4 Å resolution) revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues; INTS3 dimerization is required for recognizing longer ssDNA, and disruption of the INTS3c/INTS6c interaction impairs DSB repair. X-ray crystallography, biochemical assays (EMSA, 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, and recruits senataxin (SETX) to DSBs to resolve R-loops. Co-immunoprecipitation, in vitro binding/biochemical assays, proximity ligation, functional DSB repair assays Nucleic acids research High 39445827
2023 IntS6 (Drosophila ortholog of INTS6) over-expression blocks Integrator function at a subset of protein-coding genes by titrating PP2A subunits, thereby inhibiting Integrator phosphatase module activity only at loci where phosphatase activity is required for premature transcription termination; it has no effect on snRNA processing or attenuation at other loci. Genetic over-expression in Drosophila, RNA-seq, ChIP-seq, epistasis with canonical PP2A B-subunit over-expression Molecular cell High 37995689
2001 DICE1 (INTS6) encodes a protein containing a DEAD-box helicase motif and other helicase superfamily II motifs; GFP-fusion protein localizes preferentially to the nucleus, suggesting involvement in nuclear RNA processes. GFP fusion protein live-cell imaging, genomic/cDNA sequence analysis Oncology research Medium 11939413
1998 DBI-1 (mouse ortholog of INTS6/DICE1) protein localizes to the nucleus and, when overexpressed, diminishes the mitogenic response to IGF-1 in cells expressing the wild-type IGF-1 receptor. Immunofluorescence, overexpression, proliferation assays Experimental cell research Medium 9473344
2004 Ectopic expression of DICE1 (INTS6) via GFP-fusion constructs inhibits colony formation in lung carcinoma and prostate carcinoma cell lines, and suppresses anchorage-independent growth of IGF-IR-transformed cells dependent on IGF-I signaling. Colony formation assay, soft-agar growth assay, GFP-fusion overexpression Oncology reports Medium 15254679
2009 Re-expression of INTS6 in androgen-independent prostate cancer cells suppresses colony formation and causes G1 cell-cycle arrest; expression profiling revealed up-regulation of Wnt inhibitor CXXC4, FZD7, TCF7L1, and down-regulation of cyclin D1, linking INTS6 function to Wnt signaling and cell-cycle regulation. Colony formation assay, cell cycle analysis (FACS), gene expression profiling Cancer cell international Medium 19906297
2013 Loss of Ints6 (zebrafish ortholog) from maternal stores causes widespread de-repression of dorsal organizer genes, failure to maintain BMP ligand expression and vox/ved expression, delayed gastrulation cell movements, and severe dorsalization; restoring BMP signaling or limiting Nodal signaling rescues wild-type patterning, placing Ints6 upstream of BMP/Nodal balance in vertebrate embryonic dorsoventral patterning. Maternal-effect recessive mutation analysis in zebrafish, genetic epistasis (BMP/Nodal modulation rescue), in situ hybridization PLoS genetics High 24204286
2006 RNAi of the C. elegans INTS6 ortholog DIC-1 causes embryonic lethality with increased apoptosis and abnormal morphogenesis; DIC-1 localizes to the inner mitochondrial membrane, and its loss results in abnormal mitochondrial cristae morphology and internal vesicles, demonstrating a role in maintaining inner mitochondrial membrane topology. RNAi, cryoelectron microscopy, immunofluorescence, genetic interaction with ced-3 Development (Cambridge, England) Medium 16914495
2013 EBV-encoded miR-BART3* directly targets the 3'-UTR of DICE1 (INTS6) mRNA, causing down-regulation of DICE1 protein; inhibiting endogenous miR-BART3* with anti-miR oligonucleotides restored DICE1 expression, and forced miR-BART3* expression overcame DICE1 growth suppression and stimulated cell proliferation. 3'-UTR reporter assay, anti-miR oligonucleotide inhibition, western blot, proliferation assay International journal of cancer Medium 23280823
2015 INTS6 and its pseudogene INTS6P1 are reciprocally regulated through competition for oncomiR-17-5p (ceRNA mechanism); miR-17-5p targets both, and INTS6P1 acts as a competing endogenous RNA to derepress INTS6 in hepatocellular carcinoma. miRNA target reporter assay, overexpression/knockdown, growth/migration assays, in vivo xenograft Oncotarget Medium 25686840
2018 Small activating RNA targeting the INTS6 promoter (dsRNA-915) upregulates INTS6 expression in castration-resistant prostate cancer cells, suppresses proliferation and motility, and downregulates Wnt/β-catenin signaling; impairment of β-catenin degradation reverses these tumor suppressor effects, placing INTS6 function upstream of β-catenin. Small activating RNA transfection, cell proliferation/migration assays, western blot (β-catenin pathway) Cell cycle Medium 29895194
2021 INTS6 knockdown in colorectal cancer cells induces G1/S cell-cycle arrest and suppresses tumor growth; overexpression increases phospho-AKT and phospho-ERK levels, and pharmacological AKT or ERK inhibitors block the growth-promoting effect, placing INTS6 upstream of PI3K/AKT and MAPK pathways regulating c-Myc and CDK2. siRNA knockdown, overexpression, western blot (p-AKT, p-ERK), kinase inhibitor rescue, xenograft assay Experimental cell research Medium 34508742
2024 In C. elegans, INTS-6 is required for RAD-51 foci formation upon X-ray irradiation and for CDK-1 Tyr-15 phosphorylation, placing the Integrator subunit 6 in the DNA damage response pathway upstream of CDK-1 regulation. RNAi/loss-of-function in C. elegans, immunofluorescence (RAD-51 foci), western blot (CDK-1 pTyr15) microPublication biology Medium 39575199
2025 Conditional knockout of Ints6 in mouse nervous system disrupts early neurogenesis, cortical lamination, and synaptic development, with increased apoptosis in cortical layer 6 and altered RNAPII dynamics; CDK9 inhibitor treatment reduces RNAPII phosphorylation and rescues neurosphere overproliferation and abnormal dendritic spines caused by Ints6 deficiency, placing INTS6 in the RNAPII transcription elongation control pathway during neurogenesis. Conditional KO mouse, behavioral assays, CDK9 inhibitor rescue, RNAPII ChIP, neurosphere assays The Journal of clinical investigation High 40966122

Source papers

Stage 0 corpus · 24 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 91 23280823
2015 Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma. Oncotarget 58 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 24 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
2024 Integrator complex subunit 6 (INTS-6) mediates DNA damage response in Caenorhabditis elegans. microPublication biology 0 39575199